Indazolyl-substituted pyrroline compounds as kinase inhibitors

ABSTRACT

The present invention is directed to novel indazolyl-substituted pyrroline compounds of Formula (I): 
                         
useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

CROSS-REFERENCES TO RELATED APPLICATIONS

This patent application is a divisional of application Ser. No.10/909,537, filed on Aug. 2, 2004, now U.S. Pat. No. 7,329,657, issuedon Feb. 12, 2008, which is a divisional of nonprovisional applicationSer. No. 10/013,181, filed on Dec. 6, 2001, now U.S. Pat. No. 6,849,643,issued on Feb. 1, 2005, which claims priority from provisional patentapplication Ser. No. 60/254,166, filed on Dec. 8, 2000, all of which arehereby incorporated by reference herein.

FIELD OF THE INVENTION

This invention is directed to certain novel compounds, methods forproducing them and methods for treating or ameliorating a kinase ordual-kinase mediated disorder. More particularly, this invention isdirected to indazolyl-substituted pyrroline compounds useful asselective kinase or dual-kinase inhibitors, methods for producing suchcompounds and methods for treating or ameliorating a kinase ordual-kinase mediated disorder.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,057,614 to Davis, et. al., describes substituted pyrrolecompounds of formula I:

wherein R¹ signifies hydrogen, alkyl, aryl (limited to phenyl), aralkyl(limited to phenylalkyl), alkoxyalkyl, hydroxyalkyl, haloalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, trialkylaminoalkyl,aminoalkylaminoalkyl, azidoalkyl, acylaminoalkyl, acylthioalkyl,alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl,alkylthioalkyl, alkylsulphinylalkyl, alkylsulphonylalkyl,alkylsulphonyloxyalkyl, alkylcarbonyloxyalkyl, cyanoalkyl, amidinoalkyl,isothiocyanatoalkyl, glucopyranosyl, carboxyalkyl, alkoxycarbonylalkyl,aminocarbonylalkyl, hydroxyalkylthioalkyl, mercaptoalkylthioalkyl,arylthioalkyl or carboxyalkylthioalkyl or a group of the formula—(CH₂)_(n)—W-Het,  (a)—(CH₂)_(n)-T-C(═V)-Z,  (b)—(CH₂)_(n)—NH—C(═O)-lm, or  (c)—(CH₂)_(n)—NH—C(═NH)—Ar  (d)in which Het signifies a heterocyclyl group, W signifies NH, S or abond, T signifies NH or S, V signifies O, S, NH, NNO₂, NCN OR CHNO₂, Zsignifies alkylthio, amino, monoalkylamino or dialkylamino, lm signifies1-imidazolyl, Ar signifies aryl, and n stands for 2-6; R² signifieshydrogen, alkyl, aralkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl,aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl,alkylsulphonylaminoalkyl, arylsulphonylaminoalkyl, mercaptoalkyl,alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl,alkylthio or alkylsulphinyl; R³ signifies a carbocyclic or heterocyclicaromatic group; R⁴, R⁵, R⁶ and R⁷ each independently signify hydrogen,halogen, hydroxy, alkoxy, aryloxy, haloalkyl, nitro, amino, acylamino,monoalkylamino, dialkylamino, alkylthio, alkylsulphinyl oralkylsulphonyl; and one of X and Y signifies O and the other signifiesO, S, (H,OH) or (H,H); with the proviso that R¹ has a significancedifferent from hydrogen when R² signifies hydrogen, R³ signifies3-indolyl or 6-hydroxy-3-indolyl, R⁴, R⁵ and R⁷ each signify hydrogen,R⁶ signifies hydrogen or hydroxy and X and Y both signify O and when R²signifies hydrogen, R³ signifies 3-indolyl, R⁴, R⁵, R⁶ and R⁷ eachsignify hydrogen, X signifies (H,H) and Y signifies O; as well aspharmaceutically acceptable salts of acidic compounds of formula I withbases and of basic compounds of formula I with acids, as therapeuticallyactive substances for the use in control or prevention of inflammatory,immunological, bronchopulmonary and cardiovascular disorders.

The novel compounds of the present invention are structurally unlikethose disclosed by the Davis U.S. Pat. No. 5,057,614 patent. Inparticular, the Davis U.S. Pat. No. 5,057,614 patent discloses indolylsubstituted pyrrole compounds of formula I which may be furthersubstituted on the R³ position with a carbocyclic or heterocyclicaromatic group. The carbocyclic aromatic group denoted by R³ can be amonocyclic or polycyclic group, preferably a monocyclic or bicyclicgroup, i.e. phenyl or naphthyl, which can be substituted orunsubstituted, for example, with one or more, preferably one to three,substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,nitro, amino, acylamino, monoalkylamino, dialkylamino, alkylthio,alkylsulphinyl and alkylsulphonyl. Unlike compounds of the presentinvention, examples of carbocyclic aromatic groups denoted in the Davis'614 patent by R³ are phenyl, 2-, 3-, or 4-chlorophenyl, 3-bromophenyl,2- or 3-methylphenyl, 2,5-dimethylphenyl, 4-methoxyphenyl, 2- or3-trifluoromethylphenyl, 2-, 3-, or 4-nitrophenyl, 3-, or 4-aminophenyl,4-methylthiophenyl, 4-methylsulphinylphenyl, 4-methylsulphonylphenyl and1-, or 2-naphthyl. The heterocyclic aromatic group denoted by R³ can bea 5- or 6-membered heterocyclic aromatic group which can optionallycarry a fused benzene ring and which can be substituted orunsubstituted, for example, with one or more, preferably one to three,substituents selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,nitro, amino, acylamino, mono- or dialkylamino, alkylthio,alkylsulphinyl and alkylsulphonyl. Unlike compounds of the presentinvention, examples of heterocyclic aromatic groups denoted in the Davis'614 patent by R³ are 2-, or 3-thienyl, 3-benzothienyl,1-methyl-2-pyrrolyl, 1-benzimidazolyl, 3-indolyl, 1- or2-methyl-3-indolyl, 1-methoxymethyl-3-indolyl,1-(1-methoxyethyl)-3-indolyl, 1-(2-hydroxypropyl)-3-indolyl,1-(4-hydroxybutyl)-3-indolyl, 1-[1-(2-hydroxyethylthio)ethyl]-3-indolyl,1-[1-(2-mercaptoethylthio)ethyl]-3-indolyl,1-(1-phenylthioethyl)-3-indolyl,1-[1-(carboxymethylthio)ethyl]-3-indolyl and 1-benzyl-3-indolyl.

U.S. Pat. No. 5,721,245 to Davis, et. al., describes substituted4-[3-indolyl]-1H-pyrrolone compounds of formula I:

wherein R is hydrogen or hydroxy, R¹ and R² taken together are a groupof the formula —(CH₂)_(n)— and R⁷ is hydrogen or R¹ and R⁷ takentogether are a group of the formula —(CH₂)_(n)— and R² is hydrogen; R³is an aryl or aromatic heterocyclic group; R⁴, R⁵ and R⁶ eachindependently are hydrogen, halogen, alkyl, hydroxy, alkoxy, haloalkyl,nitro, amino, acylamino, alkylthio, alkylsulfinyl or alkylsulfonyl; R⁸is a group of the formula —(CH₂)_(p)—R⁹ or —(CH₂)_(q)—R¹¹; R⁹ ishydrogen, alkylcarbonyl, aminoalkylcarbonyl, cyano, amidino,alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, aminocarbonyl oraminothiocarbonyl; R¹⁰ is hydroxy, alkoxy, halogen, amino,monoalkylamino, dialkylamino, trialkylamino, azido, acylamino,alkylsulfonylamino, arylsulfonylamino, alkylthio, alkoxycarbonylamino,aminoacylamino, aminocarbonylamino, isothiocyanato, alkylcarbonyloxy,alkylsulfonyloxy or arylsulfonyloxy, a 5- or 6-membered saturatednitrogen-containing heterocycle attached via the nitrogen atom or agroup of the formula —U—C(V)—W; U is S or NH; V is NH, NNO₂, NCN, CHNO₂;W is amino, monoalkylamino or dialkylamino; one of X and Y is O and theother is O or (H,H); Z is CH or N; m, p and q are, independently, aninteger from 0 to 5, and n is an integer from 1 to 5, with the provisothat q and m are, independently, 2 to 5 when Z is N; as well aspharmaceutically acceptable salts of acidic compounds of formula I withbases and of basic compounds of formula I with acids, as therapeuticallyactive substances for use in control or prevention of inflammatory,immunological, bronchopulmonary and cardiovascular disorders.

The novel compounds of the present invention are structurally unlikethose disclosed by the Davis U.S. Pat. No. 5,721,245 patent. Inparticular, the Davis U.S. Pat. No. 5,721,245 patent discloses4-[3-indolyl]-1H-pyrrolone compounds of formula I which may be furthersubstituted on the R³ position with an aryl or aromatic heterocyclicgroup. The term “aryl”, alone or in combination denotes a monocyclic orpolycyclic group, preferably a monocyclic or bicyclic group, forexample, phenyl or naphthyl, which can be substituted or unsubstituted,for example, with one or more, preferably one to three, substituentsselected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, nitro, amino,acylamino, alkylthio, alkylsulfinyl and alkylsulfonyl. Unlike compoundsof the present invention, examples of such aryl groups in the Davis '245patent are phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3-bromophenyl, 2-methylphenyl, 3-methylphenyl, 2,5-dimethylphenyl,4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3-aminophenyl,4-aminophenyl, 4-methylthiophenyl, 4-methylsulfinylphenyl,4-methylsulfonylphenyl, 1-naphthyl, 2-naphthyl and the like. The term“aromatic heterocyclic” means a 5- or 6-membered heterocyclic aromaticgroup which can optionally carry a fused benzene ring and which can besubstituted or unsubstituted, for example, with one or more, preferablyone to three, substituents selected from halogen, alkyl, hydroxy,alkoxy, haloalkyl, nitro, amino, acylamino, alkylthio, alkylsulfinyl andalkylsulfonyl. Unlike compounds of the present invention, examples ofsuch heterocyclic groups in the Davis '245 patent are 2-thienyl,3-thienyl, 3-benzothienyl, 3-benzofuranyl, 2-pyrrolyl, 3-indolyl and thelike which can be unsubstituted or substituted in the manner indicated.The 5- or 6-membered saturated nitrogen containing heterocycle attachedvia the nitrogen atom can contain an additional nitrogen or oxygen or asulfur atom, examples of such heterocycles are pyrrolidino, piperidino,piperazino, morpholino and thiomorpholino.

U.S. Pat. No. 5,624,949 to Heath, Jr., et. al., describesbis-indolemaleimide derivatives of the formula:

wherein W is —O—, —S—, —SO—, —SO₂—, —CO—, C₂-C₆ alkylene, substitutedalkylene, C₂-C₆ alkenylene, -aryl-, -aryl(CH₂)_(m)O—, -heterocycle-,-heterocycle-(CH₂)_(m)O—, -fused bicyclic-, -fused bicyclic-(CH₂)_(m)O—,—NR₃—, —NOR₃—, —CONH— or —NHCO—; X and Y are independently C₁-C₄alkylene, substituted alkylene, or together, X, Y and W combine to form(CH₂)_(n)-AA-; R₁ is independently hydrogen, halo, C₁-C₄ alkyl, hydroxy,C₁-C₄ alkoxy, haloalkyl, nitro, NR₄R₅ or —NHCO(C₁-C₄)alkyl; R₂ ishydrogen, CH₃CO—, NH₂ or hydroxy; R₃ is hydrogen, (CH₂)_(m)aryl, C₁-C₄alkyl, —COO(C₁-C₄ alkyl), —CONR₄R₅, —C(C═NH)NH₂, —SO(C₁-C₄ alkyl),—SO₂(NR₄R₅) or —SO₂(C₁-C₄ alkyl); R₄ and R₅ are independently hydrogen,C₁-C₄ alkyl, phenyl, benzyl, or combine to the nitrogen to which theyare bonded to form a saturated or unsaturated 5 or 6 member ring; AA isan amino acid residue; m is independently 0, 1, 2 or 3; and n isindependently 2, 3, 4 or 5 as protein kinase C(PKC) inhibitors and asselective PKCβ-I and PKCβ-II inhibitors.

Patent application WO 00/06564 discloses disubstituted maleimidecompounds of Formula (I):

wherein R¹ represents hydrogen or alkyl; R² represents aryl, cycloalkylor a heterocycle; R³, R⁵, R⁶, R⁷ and R⁸ represent each hydrogen,halogen, hydroxy, amino, alkyl or alkoxy; and R⁴ is W, or R⁴ and R³ orR⁴ and R⁵ may form together a ring substituted by W thereon; wherein Wrepresents —(CH₂)_(i)—(Y)_(m)—(CH₂)_(n)-Z as PKCβ inhibitors.

Patent application WO 00/21927 describes 3-amino-4-arymaleimidecompounds having formula (I):

or a pharmaceutically acceptable derivative thereof, wherein: R ishydrogen, alkyl, aryl or aralkyl; R¹ is hydrogen, alkyl, aralkyl,hydroxyalkyl or alkoxyalkyl; R² is substituted or unsubstituted aryl orsubstituted or unsubstituted heterocyclyl; R³ is hydrogen, substitutedor unsubstituted alkyl, cycloalkyl, alkoxyalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl or aralkylwherein the aryl moiety is substituted or unsubstituted; or, R¹ and R³together with the nitrogen to which they are attached form a single orfused, optionally substituted, saturated or unsaturated heterocyclicring and a method for the treatment of conditions associated with a needfor inhibition of GSK-3, such as diabetes, dementias such as Alzheimer'sdisease and manic depression.

The indazolyl-substituted pyrroline compounds of the present inventionhave not been heretofore disclosed.

Accordingly, it is an object of the present invention to provideindazolyl-substituted pyrroline compounds useful as a kinase ordual-kinase inhibitor (in particular, a kinase selected from proteinkinase C or glycogen synthase kinase-3; and, more particularly, a kinaseselected from protein kinase C α, protein kinase C β-II, protein kinaseC γ or glycogen synthase kinase-3β), methods for their production andmethods for treating or ameliorating a kinase or dual-kinase mediateddisorder.

SUMMARY OF THE INVENTION

The present invention is directed to indazolyl-substituted pyrrolinecompounds of Formula (I)

wherein

-   R¹ and R² are independently selected from the group consisting of:-   hydrogen,-   C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl {wherein alkyl, alkenyl and    alkynyl are optionally substituted with one to two substituents    independently selected from the group consisting of —O—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-OH, —O—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-NH₂,    —O—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,    —O—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-SO₂—(C₁₋₁₈)alkyl,    —O—(C₁₋₈)alkyl-SO₂—NH₂, —O—(C₁₋₈)alkyl-SO₂—NH—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-SO₂—N[(C₁₋₈)alkyl]₂, —O—C(O)H, —O—C(O)—(C₁₋₈)alkyl,    —O—C(O)—NH₂, —O—C(O)—NH—(C₁₋₈)alkyl, —O—C(O)—N[(C₁₋₈)alkyl]₂,    —O—(C₁₋₈)alkyl-C(O)H, —O—(C₁₋₈)alkyl-C(O)—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-CO₂H, —O—(C₁₋₈)alkyl-C(O)—O—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-C(O)—NH₂, —O—(C₁₋₈)alkyl-C(O)—NH—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-C(O)—N[(C₁₋₈)alkyl]₂, —C(O)H, —C(O)—(C₁₋₈)alkyl,    —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SH, —S—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-OH, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH₂,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,    —S—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,    —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-OH,    —(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-NH₂,    —(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,    —(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl,    —C(O)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂,    —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl,    —SO₂—N[(C₁₋₈)alkyl]₂, —C(N)—NH₂, aryl and aryl(C₁₋₈)alkyl (wherein    aryl is optionally substituted with one to three substituents    independently selected from the group consisting of halogen,    C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted with two substituents    selected from the group consisting of hydrogen and C₁₋₈alkyl),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkoxy, hydroxy,    hydroxy(C₁₋₈)alkyl and nitro)), cyano, (halo)₁₋₃, hydroxy, nitro,    oxo, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl    and heteroaryl are optionally substituted with one to three    substituents independently selected from the group consisting of    C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted with two substituents    selected from the group consisting of hydrogen and C₁₋₈alkyl),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkoxy, hydroxy,    hydroxy(C₁₋₈)alkyl and nitro)},-   —C(O)—(C₁₋₈)alkyl, —C(O)-aryl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—O-aryl,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—NH-aryl, —C(O)—N[(C₁₋₈)alkyl]₂,    —SO₂—(C₁₋₈)alkyl, —SO₂-aryl,-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₁₋₈alkoxy, —C(O)H, —C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl,    —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂,    —SH, —S—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,    —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    amino-(C₁₋₈)alkyl- (wherein amino is substituted with two    substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl-, (halo)₁₋₃(C₁₋₈)alkoxy-, hydroxy,    hydroxy(C₁₋₈)alkyl, nitro, aryl, —(C₁₋₈)alkyl-aryl, heteroaryl and    —(C₁₋₁₈)alkyl-heteroaryl};-   with the proviso that if R² is selected from the group consisting of    hydrogen, unsubstituted C₁₋₇alkyl and —(C₁₋₇)alkyl-(halo)₁₋₃, then    R¹ is selected from the group consisting of other than hydrogen,    C₁₋₇alkyl, aryl (limited to phenyl unsubstituted or substituted with    one or more substituents selected from the group consisting of halo,    unsubstituted C₁₋₇alkyl, hydroxy, unsubstituted C₁₋₇alkoxy,    (halo)₁₋₃(C₁₋₇)alkyl, nitro, unsubstituted amino and cyano),    —(C₁₋₇)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted    or substituted with one or more substituents selected from the group    consisting of halo, unsubstituted C₁₋₇alkyl, hydroxy, C₁₋₇alkoxy,    (halo)₁₋₃(C₁₋₇)alkyl, nitro, unsubstituted amino and cyano),    —(C₁₋₇)alkyl(C₁₋₇)alkoxy, —(C₁₋₇)alkyl-hydroxy,    —(C₁₋₇)alkyl-(halo)₁₋₃, —(C₁₋₇)alkyl-amino (wherein amino is    substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₇alkyl),    —(C₁₋₇)alkyl-amino(C₁₋₇)alkylamino, —C₁₋₇alkyl-NH—C(O)—(C₁₋₇)alkyl,    —C₁₋₇alkyl-NH—SO₂—(C₁₋₇)alkyl, —(C₁₋₇)alkyl-SH,    —(C₁₋₇)alkyl-S—(C₁₋₇)alkyl, —(C₁₋₇)alkyl-SO₂—(C₁₋₁₇)alkyl,    —(C₁₋₇)alkyl-O—C(O)—(C₁₋₇)alkyl, —(C₁₋₇)alkyl-C(N),    —(C₁₋₇)alkyl-C(NH)—NH₂, —(C₁₋₇)alkyl-CO₂H,    —(C₁₋₇)alkyl-C(O)—O—(C₁₋₇)alkyl, —(C₁₋₇)alkyl-C(O)—NH₂,    —(CH₂)₂₋₆-heterocyclyl, —(CH₂)₂₋₆-T-C(V)-Z (wherein T is NH, V is O    and Z is amino (wherein amino is substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₇alkyl));-   X is selected from the group consisting of N and CR⁵;-   R³ and R⁴ are independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, —C(O)H,    —C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(NH)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SH,    —S—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl,    —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with two substituents    independently selected from the group consisting of hydrogen,    C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    amino-(C₁₋₈)alkyl- (wherein amino is substituted with two    substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl-, (halo)₁₋₃(C₁₋₈)alkoxy-, hydroxy,    hydroxy(C₁₋₈)alkyl-, nitro, aryl, —(C₁₋₈)alkyl-aryl, heteroaryl and    —(C₁₋₈)alkyl-heteroaryl;-   Y and Z are independently selected from the group consisting of O,    S, (H,OH) and (H,H); with the proviso that one of Y and Z is O and    the other is selected from the group consisting of O, S, (H,OH) and    (H,H); and,-   R⁵ is selected from the group consisting of hydrogen, halogen,-   C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl {wherein alkyl, alkenyl and    alkynyl are optionally substituted with one to two substituents    independently selected from the group consisting of amino    (substituted with two substituents selected from the group    consisting of hydrogen and C₁₋₈alkyl), cyano, halo, hydroxy, nitro,    oxo, aryl and heteroaryl},-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to two substituents independently selected from    the group consisting of C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted    with two substituents selected from the group consisting of hydrogen    and C₁₋₈alkyl), cyano, halo, hydroxy and nitro};    and pharmaceutically acceptable salts thereof.

The present invention is directed to indazolyl-substituted pyrrolinecompounds useful as a selective kinase or dual-kinase inhibitor; inparticular, a kinase selected from protein kinase C or glycogen synthasekinase-3; and, more particularly, a kinase selected from protein kinaseC α, protein kinase C β-II, protein kinase C γ or glycogen synthasekinase-3β.

The present invention is also directed to methods for producing theinstant indazolyl-substituted pyrroline compounds and pharmaceuticalcompositions and medicaments thereof.

The present invention is further directed to methods for treating orameliorating a kinase or dual-kinase mediated disorder. In particular,the method of the present invention is directed to treating orameliorating a kinase or dual-kinase mediated disorder such as, but notlimited to, cardiovascular diseases, diabetes, diabetes-associateddisorders, inflammatory diseases, immunological disorders,dermatological disorders, oncological disorders and CNS disorders.

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, R¹ and R² are independently selected from the groupconsisting of:

-   hydrogen,-   C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl {wherein alkyl, alkenyl and    alkynyl are optionally substituted with one to two substituents    independently selected from the group consisting of —O—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-NH₂,    —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-N[(C₁₋₄)alkyl]₂,    —O—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-SO₂—NH₂, —O—(C₁₋₄)alkyl-SO₂—NH—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-SO₂—N[(C₁₋₄)alkyl]₂, —O—C(O)H, —O—C(O)—(C₁₋₄)alkyl,    —O—C(O)—NH₂, —O—C(O)—NH—(C₁₋₄)alkyl, —O—C(O)—N[(C₁₋₄)alkyl]₂,    —O—(C₁₋₄)alkyl-C(O)H, —O—(C₁₋₄)alkyl-C(O)—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-CO₂H, —O—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-C(O)—NH₂, —O—(C₁₋₄)alkyl-C(O)—NH—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-C(O)—N[(C₁₋₄)alkyl]₂, —C(O)H, —C(O)—(C₁₋₄)alkyl,    —CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂,    —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SH, —S—(C₁₋₄)alkyl,    —S—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl,    —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-OH, —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH₂,    —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,    —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-N[(C₁₋₄)alkyl]₂,    —S—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,    —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-OH,    —(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-NH₂,    —(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-N[(C₁₋₄)alkyl]₂,    —(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl,    —C(O)—NH₂, —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂,    —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl,    —SO₂—N[(C₁₋₄)alkyl]₂, —C(N)—NH₂, aryl and aryl(C₁₋₄)alkyl (wherein    aryl is optionally substituted with one to three substituents    independently selected from the group consisting of halogen,    C₁₋₄alkyl, C₁₋₄alkoxy, amino (substituted with two substituents    selected from the group consisting of hydrogen and C₁₋₄alkyl),    cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,    hydroxy(C₁₋₄)alkyl and nitro)), cyano, (halo)₁₋₃, hydroxy, nitro,    oxo, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl    and heteroaryl are optionally substituted with one to three    substituents independently selected from the group consisting of    C₁₋₄alkyl, C₁₋₄alkoxy, amino (substituted with two substituents    selected from the group consisting of hydrogen and C₁₋₄alkyl),    cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,    hydroxy(C₁₋₄)alkyl and nitro)},-   —C(O)—(C₁₋₄)alkyl, —C(O)-aryl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—O-aryl,    —C(O)—NH—(C₁₋₄)alkyl, —C(O)—NH-aryl, —C(O)—N[(C₁₋₄)alkyl]₂,    —SO₂—(C₁₋₄)alkyl, —SO₂-aryl,-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,    C₁₋₄alkoxy, —C(O)H, —C(O)—(C₁₋₄)alkyl, —CO₂H, —C(O)—O—(C₁₋₄)alkyl,    —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂,    —SH, —S—(C₁₋₄)alkyl, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,    —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-NH₂,    —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂),    amino-(C₁₋₄)alkyl- (wherein amino is substituted with two    substituents independently selected from the group consisting of    hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-NH₂,    —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂),    cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,    hydroxy(C₁₋₄)alkyl, nitro, aryl, —(C₁₋₄)alkyl-aryl, heteroaryl and    —(C₁₋₄)alkyl-heteroaryl};-   with the proviso that if R² is selected from the group consisting of    hydrogen, unsubstituted C₁₋₄alkyl and —(C₁₋₄)alkyl-(halo)₁₋₃, then    R¹ is selected from the group consisting of other than hydrogen,    C₁₋₄alkyl, aryl (limited to phenyl unsubstituted or substituted with    one or more substituents selected from the group consisting of halo,    unsubstituted C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl,    nitro, unsubstituted amino and cyano), —(C₁₋₄)alkyl-aryl (wherein    aryl is limited to phenyl unsubstituted or substituted with one or    more substituents selected from the group consisting of halo,    unsubstituted C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl,    nitro, unsubstituted amino and cyano), —(C₁₋₄)alkyl(C₁₋₄)alkoxy,    —(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-amino    (wherein amino is substituted with two substituents independently    selected from the group consisting of hydrogen and C₁₋₄alkyl),    —(C₁₋₄)alkyl-amino(C₁₋₄)alkylamino, —C₁₋₄alkyl-NH—C(O)—(C₁₋₄)alkyl,    —C₁₋₄alkyl-NH—SO₂—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SH,    —(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,    —(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(N),    —(C₁₋₄)alkyl-C(NH)—NH₂, —(C₁₋₄)alkyl-CO₂H,    —(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(O)—NH₂,    —(CH₂)₂₄-heterocyclyl, —(CH₂)₂₄-T-C(V)-Z (wherein T is NH, V is O    and Z is amino (wherein amino is substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄alkyl)).

More preferably, R¹ and R² are independently selected from the groupconsisting of:

-   hydrogen,-   C₁₋₄alkyl, C₂₋₄alkenyl {wherein alkyl is substituted with one to two    substituents independently selected from the group consisting of    —O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,    —O—C(O)—(C₁₋₄)alkyl, —C(O)H, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, amino    (substituted with two substituents independently selected from the    group consisting of hydrogen, C₁₋₄alkyl, —(C₁₋₄)alkyl-OH,    —C(O)—O—(C₁₋₄)alkyl and aryl(C₁₋₄)alkyl), hydroxy, heterocyclyl,    aryl and heteroaryl (wherein heterocyclyl, aryl and heteroaryl are    optionally substituted with one to three substituents independently    selected from the group consisting of C₁₋₄alkyl and halo)},-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to two substituents independently selected from    the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino (substituted    with two substituents independently selected from the group    consisting of hydrogen and C₁₋₄alkyl), cyano, halo,    (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,    hydroxy(C₁₋₄)alkyl, aryl and heteroaryl};-   with the proviso that if R² is selected from the group consisting of    hydrogen and unsubstituted C₁₋₄alkyl, then R¹ is selected from the    group consisting of other than hydrogen, C₁₋₄alkyl, aryl (limited to    phenyl unsubstituted or substituted with one or more substituents    selected from the group consisting of halo, unsubstituted C₁₋₄alkyl,    hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, unsubstituted amino and    cyano), —(C₁₋₄)alkyl-aryl (wherein aryl is limited to phenyl    unsubstituted or substituted with one or more substituents selected    from the group consisting of halo and unsubstituted C₁₋₄alkyl),    —(C₁₋₄)alkyl(C₁₋₄)alkoxy, —(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-amino    (wherein amino is substituted with two substituents independently    selected from the group consisting of hydrogen and C₁₋₄alkyl),    —(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-CO₂H,    —(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl and —(CH₂)₂₄-heterocyclyl.

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, R¹ is selected from the group consisting ofhydrogen,

-   C₁₋₄alkyl, C₂₋₄alkenyl {wherein alkyl is substituted with one to two    substituents independently selected from the group consisting of    —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄alkyl), hydroxy, heterocyclyl, aryl and heteroaryl    (wherein heterocyclyl, aryl and heteroaryl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₄alkyl and halo)},-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to two substituents independently selected from    the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino (substituted    with two substituents independently selected from the group    consisting of hydrogen and C₁₋₄alkyl), cyano, halo,    (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,    hydroxy(C₁₋₄)alkyl, aryl and heteroaryl};-   with the proviso that if R² is selected from the group consisting of    hydrogen, unsubstituted C₁₋₄alkyl and —(C₁₋₄)alkyl-(halo)₁₋₃, then    R¹ is selected from the group consisting of other than hydrogen,    C₁₋₄alkyl, aryl (limited to phenyl unsubstituted or substituted with    one or more substituents selected from the group consisting of halo,    unsubstituted C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl,    unsubstituted amino and cyano), —(C₁₋₄)alkyl-aryl (wherein aryl is    limited to phenyl unsubstituted or substituted with one or more    substituents selected from the group consisting of halo and    unsubstituted C₁₋₄alkyl), —(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-amino    (wherein amino is substituted with two substituents independently    selected from the group consisting of hydrogen and C₁₋₄alkyl) and    —(CH₂)₂₄-heterocyclyl.

More preferably, R¹ is selected from the group consisting of hydrogen,

-   C₁₋₄alkyl, C₂₋₃alkenyl {wherein alkyl is substituted with one to two    substituents independently selected from the group consisting of    —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, amino (substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄alkyl), hydroxy, pyrrolidinyl, morpholinyl,    piperazinyl (wherein piperazinyl is optionally substituted with    methyl), phenyl, naphthalenyl, benzo[b]thienyl and quinolinyl    (wherein phenyl and benzo[b]thienyl are optionally substituted with    one to two chloro substituents)},-   phenyl, naphthalenyl, furyl, thienyl, pyridinyl, pyrimidinyl,    benzo[b]thienyl, quinolinyl and isoquinolinyl (wherein phenyl,    naphthalenyl and pyridinyl are optionally substituted with one to    two substituents independently selected from the group consisting of    C₁₋₄alkyl, C₁₋₄alkoxy, halo and hydroxy; and, wherein phenyl is    optionally substituted with one substituent selected from the group    consisting of phenyl and thienyl);-   with the proviso that if R² is selected from the group consisting of    hydrogen, unsubstituted C₁₋₄alkyl and —(C₁₋₄)alkyl-(halo)₁₋₃, then    R¹ is selected from the group consisting of other than hydrogen,    C₁₋₄alkyl, phenyl (wherein phenyl is unsubstituted or substituted    with one or more substituents selected from the group consisting of    halo, unsubstituted C₁₋₄alkyl, hydroxy and C₁₋₄alkoxy),    —(C₁₋₄)alkyl-phenyl (wherein phenyl is unsubstituted or substituted    with one or more chloro substituents), —(C₁₋₄)alkyl-hydroxy,    —(C₁₋₄)alkyl-amino (wherein amino is substituted with two    substituents independently selected from the group consisting of    hydrogen and C₁₋₄alkyl) and —(CH₂)₂₄-heterocyclyl.

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, R² is selected from the group consisting of:

-   hydrogen,-   C₁₋₄alkyl {wherein alkyl is substituted with one to two substituents    independently selected from the group consisting of —O—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,    —O—C(O)—(C₁₋₄)alkyl, —C(O)H, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, amino    (substituted with two substituents independently selected from the    group consisting of hydrogen, C₁₋₄alkyl, —(C₁₋₄)alkyl-OH,    —C(O)—O—(C₁₋₄)alkyl and aryl(C₁₋₄)alkyl), hydroxy and heterocyclyl    (wherein heterocyclyl is optionally substituted with one to two    C₁₋₄alkyl substituents)} and heteroaryl;-   with the proviso that if R² is selected from the group consisting of    hydrogen and unsubstituted C₁₋₄alkyl, then R¹ is selected from the    group consisting of other than hydrogen, C₁₋₄alkyl, aryl (limited to    phenyl unsubstituted or substituted with one or more substituents    selected from the group consisting of halo, unsubstituted C₁₋₄alkyl,    hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro, unsubstituted    amino and cyano), —(C₁₋₄)alkyl-aryl (wherein aryl is limited to    phenyl unsubstituted or substituted with one or more substituents    selected from the group consisting of halo, unsubstituted C₁₋₄alkyl,    hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro, unsubstituted    amino and cyano), —(C₁₋₄)alkyl(C₁₋₄)alkoxy, —(C₁₋₄)alkyl-hydroxy,    —(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-amino (wherein amino is    substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄alkyl),    —(C₁₋₄)alkyl-amino(C₁₋₄)alkylamino, —C₁₋₄alkyl-NH—C(O)—(C₁₋₄)alkyl,    —C₁₋₄alkyl-NH—SO₂—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SH,    —(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,    —(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(N),    —(C₁₋₄)alkyl-C(NH)—NH₂, —(C₁₋₄)alkyl-CO₂H,    —(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(O)—NH₂,    —(CH₂)₂₋₄-heterocyclyl, —(CH₂)₂₄-T-C(V)-Z (wherein T is NH, V is O    and Z is amino (wherein amino is substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄alkyl)).

More preferably, R² is selected from the group consisting of:

-   hydrogen,-   C₁₋₄alkyl {wherein alkyl is substituted with one to two substituents    independently selected from the group consisting of —O—(C₁₋₄)alkyl,    —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,    —O—C(O)—(C₁₋₄)alkyl, —C(O)H, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, amino    (substituted with two substituents independently selected from the    group consisting of hydrogen, C₁₋₄alkyl, —(C₁₋₄)alkyl-OH,    —C(O)—O—(C₁₋₄)alkyl and phenyl(C₁₋₄)alkyl), hydroxy, pyrrolidinyl,    1,3-dioxolanyl, morpholinyl and piperazinyl (wherein piperazinyl is    optionally substituted with methyl)} and pyridinyl;-   with the proviso that if R² is selected from the group consisting of    hydrogen and unsubstituted C₁₋₄alkyl, then R¹ is selected from the    group consisting of other than hydrogen, C₁₋₄alkyl, aryl (limited to    phenyl unsubstituted or substituted with one or more substituents    selected from the group consisting of halo, unsubstituted C₁₋₄alkyl,    hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro, unsubstituted    amino and cyano), —(C₁₋₄)alkyl-aryl (wherein aryl is limited to    phenyl unsubstituted or substituted with one or more substituents    selected from the group consisting of halo, unsubstituted C₁₋₄alkyl,    hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro, unsubstituted    amino and cyano), —(C₁₋₄)alkyl(C₁₋₄)alkoxy, —(C₁₋₄)alkyl-hydroxy,    —(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-amino (wherein amino is    substituted with two substituents independently selected from the    group consisting of hydrogen and C₁₋₄alkyl),    —(C₁₋₄)alkyl-amino(C₁₋₄)alkylamino, —C₁₋₄alkyl-NH—C(O)—(C₁₋₄)alkyl,    —C₁₋₄alkyl-NH—SO₂—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SH,    —(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,    —(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(N),    —(C₁₋₄)alkyl-C(NH)—NH₂, -(C₁₋₄)alkyl-CO₂H,    —(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(O)—NH₂,    —(CH₂)₂₋₄-heterocyclyl, —(CH₂)₂₋₄-T-C(V)-Z (wherein T is NH, V is O    and Z is amino (wherein amino is substituted with two substituents    independently selected from the group consisting of hydrogen and    C₁₋₄alkyl)).

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, X is selected from the group consisting of N andCR⁵.

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, R³ and R⁴ are independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,—C(O)H, —C(O)—(C₁₋₄)alkyl, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,—C(NH)—NH₂, —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SH,—S—(C₁₋₄)alkyl, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl,—SO₂—N[(C₁₋₄)alkyl]₂, amino (substituted with two substituentsindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-NH₂, —C(O)—(C₁₋₄)alkyl,—C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(O)—NH—(C₁₋₄)alkyl,—C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl,—SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂), amino-(C₁₋₄)alkyl- (wherein aminois substituted with two substituents independently selected from thegroup consisting of hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,—(C₁₋₄)alkyl-NH₂, —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,—C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂), cyano, halo,(halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,hydroxy(C₁₋₄)alkyl, nitro, aryl, —(C₁₋₄)alkyl-aryl, heteroaryl and—(C₁₋₄)alkyl-heteroaryl.

More preferably, R³ and R⁴ are independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, cyano and halogen.

Most preferably, R³ and R⁴ are independently selected from the groupconsisting of hydrogen, methyl, methoxy, cyano and chloro.

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, Y and Z are independently selected from the groupconsisting of O, S, (H,OH) and (H,H); with the proviso that one of Y andZ is O, and the other is selected from the group consisting of O, S,(H,OH) and (H,H).

More preferably, Y and Z are independently selected from the groupconsisting of O and (H,H); with the proviso that one of Y and Z is O,and the other is selected from the group consisting of O and (H,H).

Preferred embodiments of the present invention include compounds ofFormula (I) wherein, R⁵ is selected from the group consisting ofhydrogen, halogen,

-   C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl {wherein alkyl, alkenyl and    alkynyl are optionally substituted with one to two substituents    independently selected from the group consisting of amino    (substituted with two substituents selected from the group    consisting of hydrogen and C₁₋₄alkyl), cyano, halo, hydroxy, nitro,    oxo, aryl and heteroaryl},-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to two substituents independently selected from    the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino (substituted    with two substituents selected from the group consisting of hydrogen    and C₁₋₄alkyl), cyano, halo, hydroxy and nitro}.

More preferably, R⁵ is selected from the group consisting of C₁₋₄alkyland aryl.

Most preferably, R⁵ is selected from the group consisting of methyl andnapthalenyl.

Exemplified compounds of Formula (I) include compounds selected fromFormula (Ia) (N1 and N2 for the R² substituent indicate that R² isattached to the N1- or N2-position of the indazole ring, respectively):

Formula (Ia) wherein R¹, R², R³ and R⁴ are selected from No. R¹ R² R³ R⁴1 H₂C═CH N1—[Me₂NCH₂CH(OH)CH₂] H H; 2 H₂C═CH N1—[MeNHCH₂CH(OH)CH₂] H H;3 H₂C═CH N1—[Me₂N(CH₂)₃] H H; 4 H₂C═CH N1—[Me₂NCH₂CH(OH)CH₂] 5-Cl H; 5H₂C═CH N1—[Me₂N(CH₂)₃] 5-Cl H; 6 H₂C═CH N1—[Me₂N(CH₂)₃] H 5-Cl; 7H₂C═CHCH₂ N1—[Me₂N(CH₂)₃] H H; 8 3-thienyl N1—[Me₂N(CH₂)₃] H H; 92-thienyl N1—[Me₂N(CH₂)₃] H H; 10 H₂C═CH N1—[Me₂N(CH₂)₃] H 4-Cl; 113-furyl N1—[Me₂N(CH₂)₃] H H; 12 3-pyridinyl N1—[Me₂N(CH₂)₃] H H; 133-pyridinyl N1—[Me₂N(CH₂)₃] H 5-Cl; 14 2-naphthyl N1—[Me₂N(CH₂)₃] H H;15 1-naphthyl N1—[Me₂N(CH₂)₃] H H; 16 4-isoquinolinyl N1—[Me₂N(CH₂)₃] HH; 18 3-pyridinyl N1—[Me₂N(CH₂)₃] H 6-Cl; 19 3-quinolinylN1—[Me₂N(CH₂)₃] H H; 21 3-quinolinyl N1—[Et₂N(CH₂)₃] H H; 223-quinolinyl N1—[(4-morpholinyl)(CH₂)₃] H H; 23 3-quinolinylN1—[HCO(CH₂)₂] H H; 24 3-quinolinyl N1—[(1,3-dioxolan-2-yl)(CH₂)₂] H H;25 3-pyridinyl N1—[Me₂N(CH₂)₃] H 5-OMe; 26 3-pyridinyl-CH₂N1—[Me₂N(CH₂)₃] H H; 27 (6-CH₃)pyridin-3-yl N1—[Me₂N(CH₂)₃] H H; 28H₂C═CH N1—[Me₂N(CH₂)₃] H H; 29 H₂C═CH N1—[Me₂N(CH₂)₃] H 5-Cl; 312-pyridinyl N1—[Me₂N(CH₂)₃] H H; 32 4-pyridinyl N1—[Me₂N(CH₂)₃] H H; 332-thienyl N1—[Me₂N(CH₂)₃] H 5-Cl; 34 5-pyrimidinyl N1—[Me₂N(CH₂)₃] H H;35 (5-Br)pyridin-2-yl N1—[Me₂N(CH₂)₃] H H; 38 Me₂N(CH₂)₃ N1—H H H; 39 HN1—[Me₂NCH₂CH(OH)CH₂] 5-Cl H; 40 Me N1—[Me₂NCH₂CH(OH)CH₂] H H; 41 MeN1—[Me₂NCH₂CH(OH)CH₂] H H; 42 Me N1—[Me₂N(CH₂)₃] H H; 43 MeN1—[Me₂N(CH₂)₃] H 5-Cl; 44 Et N1—[Me₂N(CH₂)₃] H H; 45 Ph N1—[Me₂N(CH₂)₃]H H; 46 Et N1—[Me₂N(CH₂)₃] H 5-Cl; 47 H N1—[Me₂N(CH₂)₃] H 5-Cl; 48 PhN1—[Me₂N(CH₂)₃] H 5-Cl; 49 H N1—[Me₂N(CH₂)₃] H 4-Cl; 50 i-propylN1—[Me₂N(CH₂)₃] H 5-Cl; 51 Et N1—[Me₂N(CH₂)₃] H 5-Me; 52 HO(CH₂)₂N1—[Me₂N(CH₂)₃] H H; 53 2-MePh N1—[Me₂N(CH₂)₃] H H; 54 3-BrPhN1—[Me₂N(CH₂)₃] H H; 55 H N1—[Me₂N(CH₂)₃] H H; 56 Me N1—[Me₂N(CH₂)₃] HH; 59 Me₂N(CH₂)₃ N1-3-pyridinyl H H; 60 3-benzo[b]thienylN1—[Me₂N(CH₂)₃] H H; 61 3-Ph-Ph N1—[Me₂N(CH₂)₃] H H; 622,5-diMe-pyridin-3-yl N1—[Me₂N(CH₂)₃] H H; 63 6-OMe-naphth-2-ylN1—[Me₂N(CH₂)₃] H H; 64 6-OH-naphth-2-yl N1—[Me₂N(CH₂)₃] H H; 656-quinolinyl N1—[Me₂N(CH₂)₃] H H; 66 1-naphthyl-CH₂ N1—[Me₂N(CH₂)₃] H H;67 2-quinolinyl-CH₂ N1—[Me₂N(CH₂)₃] H H; 68 3-pyridinylN1—[(4-morpholinyl)(CH₂)₃] H H; 69 Et N1—[(4-morpholinyl)(CH₂)₃] H 5-Cl;70 2-naphthyl N1—[(4-morpholinyl)(CH₂)₃] H H; 71 2,6-diCl-Ph-CH₂N1—[Me₂N(CH₂)₃] H H; 72 3-(thien-3-yl)-Ph N1—[Me₂N(CH₂)₃] H H; 735-Cl-benzo[b]thien-3-yl-CH₂ N1—[Me₂N(CH₂)₃] H H; 74 Me N1—[HO(CH₂)₃] H5-Cl; 75 Me N1—[(1-pyrrolidinyl)(CH₂)₃ H 5-Cl; 76 Me N1—[AcO(CH₂)₃] H5-Cl; 77 Me N1—[(4-Me-piperazin-1-yl)(CH₂)₃] H 5-Cl; 78 MeN1—[(4-morpholinyl)(CH₂)₃] H 5-Cl; 79 Me N1—[(HOCH₂CH₂)MeN(CH₂)₃] H5-Cl; 80 Me N1—[MeHN(CH₂)₃] H 5-Cl; 81 Et N1—[Me₂N(CH₂)₃] H 5-OMe; 82 MeN1—[(PhCH₂)MeN(CH₂)₃] H 5-Cl; 83 MeHN(CH₂)₂O(CH₂)₂N1—[MeHN(CH₂)₂O(CH₂)₂] H H; 84 2-naphthyl N1—[HO(CH₂)₃] H H; 852-naphthyl N1—[(1-pyrrolidinyl)(CH₂)₃] H H; 86 (4-morpholinyl)(CH₂)₃N1-Et 5-Cl H; 87 (4-Me-piperazin-1-yl-(CH₂)₃ N1-Et 5-Cl H; 88 2-naphthylN1—[HOCH₂CH₂)MeN(CH₂)₃] H H; 89 2-naphthylN1—[(4-Me-piperazin-1-yl-(CH₂)₃] H H; 90 Et N1—[Me₂N(CH₂)₃] H 6-Cl; 912-naphthyl N1—[HO(CH₂)₄] H H; 92 3-benzo[b]thienyl N1—[HO(CH₂)₄] H H; 933-benzo[b]thienyl N1—[Me₂N(CH₂)₄] H H; 94 3-pyridinyl N1—[HO(CH₂)₃] H H;95 Et N1—[Me₂N(CH₂)₃] H 7-Cl; 96 (1-pyrrolidinyl)(CH₂)₃ N1-Et 5-Cl H; 972-naphthyl N1—[Me₂N(CH₂)₃] H H; 98 Et N1—[Me₂N(CH₂)₃] H 5-CN; 993-benzo[b]thienyl N1—[HO(CH₂)₂] H H; 100 2-naphthyl N1—[HO(CH₂)₂] H H;101 2-naphthyl N1—[Me₂N(CH₂)₂] H H; 102 2-pyridinyl N1—[HO(CH₂)₃] H H;103 3-benzo[b]thienyl N1—[Me₂N(CH₂)₂] H H; 104 3-benzo[b]thienyl H H H;105 4-isoquinolinyl N1—[HO(CH₂)₃] H H; 106 3-pyridinylN1—[HO(CH₂)₂O(CH₂)₂] H H; 107 3-quinolinyl N1—[HO(CH₂)₃] H H; 1083-benzo[b]thienyl N1—[HO(CH₂)₃] H H; 109 3-pyridinyl N1—[HO(CH₂)₃] H H;110 3-pyridinyl N1—[HO(CH₂)₂] H H; 111 3-pyridinyl N1—[HO(CH₂)₄] H H;112 3-pyridinyl N1—[OHC(CH₂)₂] H H; 113 3-pyridinyl N1—[HO₂C(CH₂)₂] H H;114 3-pyridinyl N1—[(HOCH₂CH₂)MeN(CH₂)₃] H H; 115 3-pyridinylN1—[BocNH(CH₂)₃] H H; 116 3-benzo[b]thienyl N1—[MeO₂C(CH₂)₂] H H; 1173-pyridinyl N1—[MeO(CH₂)₃] H H; 118 3-pyridinyl H H H; 119 3-pyridinylN1—[AcO(CH₂)₃] H H; 120 4-morpholinyl)(CH₂)₃ N2-Et 5-Cl H; 1213-pyridinyl N2—[HO(CH₂)₃] H H; 122 2-naphthyl N2—[Me₂N(CH₂)₂] H H; 1233-benzo[b]thienyl N2—[Me₂N(CH₂)₂] H H; or, 124 Me N2—[HO(CH₂)₃] H 5-Cl;and pharmaceutically acceptable salts thereof.

Exemplified compounds of Formula (I) include compounds selected fromFormula (Ib) (N1 and N2 for the R² substituent indicate that R² isattached to the N1- or N2-position of the indazole ring, respectively):

Formula (Ib) wherein Y, Z, R¹, R², R³ and R⁴ are selected from No. Y ZR¹ R² R³ R⁴  36 H, H O 2-thienyl N1—[Me₂N(CH₂)₃] H H;  37 O H, H2-thienyl N1—[Me₂N(CH₂)₃] H H; or, 125 O H, H 3-pyridinylN1—[Me₂N(CH₂)₃] H H; and pharmaceutically acceptable salts thereof.

Exemplified compounds of Formula (I) include compounds selected fromFormula (Ic) (N1 and N2 for the R² substituent indicate that R² isattached to the N1- or N2-position of the indazole ring, respectively):

Formula (Ic) wherein X, R¹, R², R³, R⁴ and R⁵ are selected from No. X R¹R² R³ R⁴ R⁵ 17 C—R⁵ 3-pyridinyl N1—[Me₂N(CH₂)₃] H H 2-naphthyl; 20 C—R⁵3-pyridinyl N1—[Me₂N(CH₂)₃] H 5-Cl CH₃; 30 N H₂C═CHCH₂ N1—[Me₂N(CH₂)₃] HH —; 57 N H N1═[Me₂N(CH₂)₃] H H —; or, 58 N Me₂N(CH₂)₃ N1—[Me₂N(CH₂)₃] HH  ; and pharmaceutically acceptable salts thereof.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts.” FDA approved pharmaceutically acceptable salt forms(Ref. International J. Pharm. 1986, 33, 201-217; J. Pharm. Sci., 1977,January, 66(1), p 1) include pharmaceutically acceptable acidic/anionicor basic/cationic salts. Pharmaceutically acceptable acidic/anionicsalts include, and are not limited to acetate, benzenesulfonate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate,carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, glyceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, malate, maleate, mandelate, mesylate, methylbromide,methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate,pantothenate, phosphate/diphospate, polygalacturonate, salicylate,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,tosylate and triethiodide. Pharmaceutically acceptable basic/cationicsalts include, and are not limited to aluminum, benzathine, calcium,chloroprocaine, choline, diethanolamine, ethylenediamine, lithium,magnesium, meglumine, potassium, procaine, sodium and zinc. Other saltsmay, however, be useful in the preparation of compounds according tothis invention or of their pharmaceutically acceptable salts. Organic orinorganic acids also include, and are not limited to, hydriodic,perchloric, sulfuric, phosphoric, propionic, glycolic, methanesulfonic,hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic, p-toluenesulfonic,cyclohexanesulfamic, saccharinic or trifluoroacetic acid.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. Where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form orindividual enantiomers may be prepared by standard techniques known tothose skilled in the art, for example, by enantiospecific synthesis orresolution, formation of diastereomeric pairs by salt formation with anoptically active acid, followed by fractional crystallization andregeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.It is to be understood that all such isomers and mixtures thereof areencompassed within the scope of the present invention.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents and such solvates arealso intended to be encompassed within the scope of this invention.

Unless specified otherwise, the term “alkyl” refers to a saturatedstraight or branched chain consisting solely of 1-8 hydrogen substitutedcarbon atoms; preferably, 1-6 hydrogen substituted carbon atoms; and,most preferably, 14 hydrogen substituted carbon atoms. The term“alkenyl” refers to a partially unsaturated straight or branched chainconsisting solely of 2-8 hydrogen substituted carbon atoms that containsat least one double bond. The term “alkynyl” refers to a partiallyunsaturated straight or branched chain consisting solely of 2-8 hydrogensubstituted carbon atoms that contains at least one triple bond. Theterm “alkoxy” refers to —O-alkyl, where alkyl is as defined supra. Theterm “hydroxyalkyl” refers to radicals wherein the alkyl chainterminates with a hydroxy radical of the formula HO-alkyl, where alkylis as defined supra. Alkyl, alkenyl and alkynyl chains are optionallysubstituted within the alkyl chain or on a terminal carbon atom.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic alkyl ring consisting of 3-8 hydrogen substituted carbonatoms or a saturated or partially unsaturated bicyclic ring consistingof 9 or 10 hydrogen substituted carbon atoms. Examples include, and arenot limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “heterocyclyl” refers to a saturated or partially unsaturatedring having five members of which at least one member is a N, O or Satom and which optionally contains one additional O atom or one, two orthree additional N atoms, a saturated or partially unsaturated ringhaving six members of which one, two or three members are a N atom, asaturated or partially unsaturated bicyclic ring having nine members ofwhich at least one member is a N, O or S atom and which optionallycontains one, two or three additional N atoms or a saturated orpartially unsaturated bicyclic ring having ten members of which one, twoor three members are a N atom. Examples include, and are not limited to,pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl or piperazinyl.

The term “aryl” refers to an aromatic monocyclic ring containing 6hydrogen substituted carbon atoms, an aromatic bicyclic ring systemcontaining 10 hydrogen substituted carbon atoms or an aromatic tricyclicring system containing 14 hydrogen substituted carbon atoms. Examplesinclude, and are not limited to, phenyl, naphthalenyl or anthracenyl.

The term “heteroaryl” refers to an aromatic monocyclic ring systemcontaining five members of which at least one member is a N, O or S atomand which optionally contains one, two or three additional N atoms, anaromatic monocyclic ring having six members of which one, two or threemembers are a N atom, an aromatic bicyclic ring having nine members ofwhich at least one member is a N, O or S atom and which optionallycontains one, two or three additional N atoms or an aromatic bicyclicring having ten members of which one, two or three members are a N atom.Examples include, and are not limited to, furyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl,benzo[b]thienyl, quinolinyl, isoquinolinyl or quinazolinyl.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g., aralkyl, alkylamino) it shallbe interpreted as including those limitations given above for “alkyl”and “aryl.” Designated numbers of carbon atoms (e.g., C₁-C₆) shall referindependently to the number of carbon atoms in an alkyl or cycloalkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

Under standard nomenclature rules used throughout this disclosure, theterminal portion of the designated side chain is described firstfollowed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁₋₆alkylamidoC₁₋₆alkyl” substituent refersto a group of the formula:

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

An embodiment of the invention is a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and any of thecompounds described above. Illustrative of the invention is apharmaceutical composition made by mixing any of the compounds describedabove and a pharmaceutically acceptable carrier. Another illustration ofthe invention is a process for making a pharmaceutical compositioncomprising mixing any of the compounds described above and apharmaceutically acceptable carrier. Further illustrative of the presentinvention are pharmaceutical compositions comprising one or morecompounds of this invention in association with a pharmaceuticallyacceptable carrier.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The compounds of the present invention are selective kinase ordual-kinase inhibitors useful in a method for treating or ameliorating akinase or dual-kinase mediated disorder. In particular, the kinase isselected from protein kinase C or glycogen synthase kinase-3. Moreparticularly, the kinase is selected from protein kinase C α, proteinkinase C β-II, protein kinase C γ or glycogen synthase kinase-3β.

Protein Kinase C isoforms

Protein kinase C is known to play a key role in intracellular signaltransduction (cell-cell signaling), gene expression and in the controlof cell differentiation and growth. The PKC family is composed of twelveisoforms that are further classified into 3 subfamilies: the calciumdependent classical PKC isoforms alpha (α), beta-I (β-I), beta-II (β-II)and gamma (γ); the calcium independent PKC isoforms delta (δ), epsilon(ε), eta (η), theta (θ) and mu (μ); and, the atypical PKC isoforms zeta(ζ), lambda (λ) and iota (ι).

Certain disease states tend to be associated with elevation ofparticular PKC isoforms. The PKC isoforms exhibit distinct tissuedistribution, subcellular localization and activation-dependentcofactors. For example, the a and β isoforms of PKC are selectivelyinduced in vascular cells stimulated with agonists such as vascularendothelial growth factor (VEGF) (P. Xia, et al., J. Clin. Invest.,1996, 98, 2018) and have been implicated in cellular growth,differentiation, and vascular permeability (H. Ishii, et al., J. Mol.Med., 1998, 76, 21). The elevated blood glucose levels found in diabetesleads to an isoform-specific elevation of the β-II isoform in vasculartissues (Inoguchi, et al., Proc. Natl. Acad. Sci. USA, 1992, 89,11059-11065). A diabetes-linked elevation of the β isoform in humanplatelets has been correlated with their altered response to agonists(Bastyr III, E. J. and Lu, J., Diabetes, 1993, 42, (Suppl. 1) 97A). Thehuman vitamin D receptor has been shown to be selectively phosphorylatedby PKCβ. This phosphorylation has been linked to alterations in thefunctioning of the receptor (Hsieh, et al., Proc. Natl. Acad. Sci. USA,1991, 88, 9315-9319; Hsieh, et al., J. Biol. Chem., 1993, 268,15118-15126). In addition, the work has shown that the β-II isoform isresponsible for erythroleukemia cell proliferation while the α isoformis involved in megakaryocyte differentiation in these same cells(Murray, et al., J. Biol. Chem., 1993, 268, 15847-15853).

Cardiovascular Diseases

PKC activity plays an important role in cardiovascular diseases.Increased PKC activity in the vasculature has been shown to causeincreased vasoconstriction and hypertension (Bilder, G. E., et al., J.Pharmacol. Exp. Ther., 1990, 252, 526-530). PKC inhibitors blockagonist-induced smooth muscle cell proliferation (Matsumoto, H. andSasaki, Y., Biochem. Biophys. Res. Commun., 1989, 158, 105-109). PKC Ptriggers events leading to induction of Egr-1 (Early Growth Factor-1)and tissue factor under hypoxic conditions (as part of the oxygendeprivation-mediated pathway for triggering procoagulant events) (Yan,S-F, et al., J. Biol. Chem., 2000, 275, 16, 11921-11928). PKC β issuggested as a mediator for production of PAI-1 (Plaminogen ActivatorInhibitor-1) and is implicated in the development of thrombosis andatherosclerosis (Ren, S, et al., Am. J. Physiol., 2000, 278, (4, Pt. 1),E656-E662). PKC inhibitors are useful in treating cardiovascularischemia and improving cardiac function following ischemia (Muid, R. E.,et al., FEBS Lett., 1990, 293, 169-172; Sonoki, H. et al., Kokyu-ToJunkan, 1989, 37, 669-674). Elevated PKC levels have been correlatedwith an increased platelet function response to agonists (Bastyr III, E.J. and Lu, J., Diabetes, 1993, 42, (Suppl. 1) 97A). PKC has beenimplicated in the biochemical pathway in the platelet-activating factor(PAF) modulation of microvascular permeability (Kobayashi, et al., Amer.Phys. Soc., 1994, H1214-H1220). PKC inhibitors affect agonist-inducedaggregation in platelets (Toullec, D., et al., J. Biol. Chem., 1991,266, 15771-15781). Accordingly, PKC inhibitors may be indicated for usein treating cardiovascular disease, ischemia, thrombotic conditions,atherosclerosis and restenosis.

Diabetes

Excessive activity of PKC has been linked to insulin signaling defectsand therefore to the insulin resistance seen in Type II diabetes(Karasik, A., et al., J. Biol. Chem., 1990, 265, 10226-10231; Chen, K.S., et al., Trans. Assoc. Am. Physicians, 1991, 104, 206-212; Chin, J.E., et al., J. Biol. Chem., 1993, 268, 6338-6347).

Diabetes-Associated Disorders

Studies have demonstrated an increase in PKC activity in tissues knownto be susceptible to diabetic complications when exposed tohyperglycemic conditions (Lee, T-S., et al., J. Clin. Invest, 1989, 83,90-94; Lee, T-S., et al., Proc. Natl. Acad. Sci. USA, 1989, 86,5141-5145; Craven, P. A. and DeRubertis, F. R., J. Clin. Invest., 1989,87, 1667-1675; Wolf, B. A., et al., J. Clin. Invest., 1991, 87, 31-38;Tesfamariam, B., et al., J. Clin. Invest., 1991, 87, 1643-1648). Forexample, activation of the PKC-β-II isoform plays an important role indiabetic vascular complications such as retinopathy (Ishii, H., et al.,Science, 1996, 272, 728-731) and PKCβ has been implicated in developmentof the cardiac hypertrophy associated with heart failure (X. Gu, et al.,Circ. Res., 1994, 75, 926; R. H. Strasser, et al., Circulation, 1996,94, I551). Overexpression of cardiac PKCβII in transgenic mice causedcardiomyopathy involving hypertrophy, fibrosis and decreased leftventricular function (H. Wakasaki, et al., Proc. Natl. Acad. Sci. USA,1997, 94, 9320).

Inflammatory Diseases

PKC inhibitors block inflammatory responses such as the neutrophiloxidative burst, CD3 down-regulation in T-lymphocytes andphorbol-induced paw edema (Twoemy, B., et al., Biochem. Biophys. Res.Commun., 1990, 171, 1087-1092; Mulqueen, M. J., et al. Agents Actions,1992, 37, 85-89). PKC β has an essential role in the degranulation ofbone marrow-derived mast cells, thus affecting cell capacity to produceIL-6 (Interleukin-6) (Nechushtan, H., et al., Blood, 2000 (March), 95,5, 1752-1757). PKC plays a role in enhanced ASM (Airway Smooth Muscle)cell growth in rat models of two potential risks for asthma:hyperresponsiveness to contractile agonists and to growth stimuli (Ren,S, et al., Am. J. Physiol., 2000, 278, (4, Pt. 1), E656-E662). PKC β-1overexpression augments an increase in endothelial permeability,suggesting an important function in the regulation of the endothelialbarrier (Nagpala, P. G., et al., J. Cell Physiol., 1996, 2, 249-55). PKCβ mediates activation of neutrophil NADPH oxidase by PMA and bystimulation of Fcγ receptors in neutrophils (Dekker, L. V., et al.,Biochem. J., 2000, 347, 285-289). Thus, PKC inhibitors may be indicatedfor use in treating inflammation and asthma.

Immunological Disorders

PKC may be useful in treating or ameliorating certain immunologicaldisorders. While one study suggests that HCMV (Human Cytomegalovirus)inhibition is not correlated with PKC inhibition (Slater, M. J., et al.,Biorg. & Med. Chem., 1999, 7, 1067-1074), another study showed that thePKC signal transduction pathway synergistically interacted with thecAMP-dependent PKA pathway to activate or increase HIV-1 transcriptionand viral replication and was abrogated with a PKC inhibitor (Rabbi, M.F., et al., Virology, 1998 (June 5), 245, 2, 257-69). Therefore, animmunological disorder may be treated or ameliorated as a function ofthe affected underlying pathway's response to up- or down-regulation ofPKC.

PKC β deficiency also results in an immunodeficiency characterized byimpaired humoral immune responses and a reduced B cell response, similarto X-linked immunodeficiency in mice, playing an important role inantigen receptor-mediated signal transduction (Leitges, M., et al.,Science (Wash., D.C.), 1996, 273, 5276, 788-789). Accordingly,transplant tissue rejection may be ameliorated or prevented bysuppressing the immune response using a PKC β inhibitor.

Dermatological Disorders

Abnormal activity of PKC has been linked to dermatological disorderscharacterized by abnormal proliferation of keratinocytes, such aspsoriasis (Horn, F., et al., J. Invest. Dermatol., 1987, 88, 220-222;Raynaud, F. and Evain-Brion, D., Br. J. Dermatol., 1991, 124, 542-546).PKC inhibitors have been shown to inhibit keratinocyte proliferation ina dose-dependent manner (Hegemann, L., et al., Arch. Dermatol. Res.,1991, 283, 456-460; Bollag, W. B., et al., J. Invest. Dermatol., 1993,100, 240-246).

Oncological Disorders

PKC activity has been associated with cell growth, tumor promotion andcancer (Rotenberg, S. A. and Weinstein, I. B., Biochem. Mol. Aspects.Sel. Cancer, 1991, 1, 25-73; Ahmad, et al., Molecular Pharmacology,1993, 43, 858-862); PKC inhibitors are known to be effective inpreventing tumor growth in animals (Meyer, T., et al., Int. J. Cancer,1989, 43, 851-856; Akinagaka, S., et al., Cancer Res., 1991, 51,4888-4892). PKC β-1 and β-2 expression in differentiated HD3 coloncarcinoma cells blocked their differentiation, enabling them toproliferate in response to basic FGF (Fibroblast Growth Factor) likeundifferentiated cells, increasing their growth rate and activatingseveral MBP (Myelin-Basic Protein) kinases, including p57 MAP(Mitogen-Activated Protein) kinase (Sauma, S., et al., Cell GrowthDiffer., 1996, 7, 5, 587-94). PKC a inhibitors, having an additivetherapeutic effect in combination with other anti-cancer agents,inhibited the growth of lymphocytic leukemia cells (Konig, A., et al.,Blood, 1997, 90, 10, Suppl. 1 Pt. 2). PKC inhibitors enhanced MMC(Mitomycin-C) induced apoptosis in a time-dependent fashion in a gastriccancer cell-line, potentially indicating use as agents forchemotherapy-induced apoptosis (Danso, D., et al., Proc. Am. Assoc.Cancer Res., 1997, 38, 88 Meet., 92). Therefore, PKC inhibitors may beindicated for use in ameliorating cell and tumor growth, in treating orameliorating cancers (such as leukemia or colon cancer) and as adjunctsto chemotherapy.

PKC α (by enhancing cell migration) may mediate some proangiogeniceffects of PKC activation while PKC 6 may direct antiangiogenic effectsof overall PKC activation (by inhibiting cell growth and proliferation)in capillary endothelial cells, thus regulating endothelialproliferation and angiogenesis (Harrington, E. O., et al., J. Biol.Chem., 1997, 272, 11, 7390-7397). PKC inhibitors inhibit cell growth andinduce apoptosis in human glioblastoma cell lines, inhibit the growth ofhuman astrocytoma xenografts and act as radiation sensitizers inglioblastoma cell lines (Begemann, M., et al., Anticancer Res. (Greece),1998 (July-August), 18, 4A, 2275-82). PKC inhibitors, in combinationwith other anti-cancer agents, are radiation and chemosensitizers usefulin cancer therapy (Teicher, B. A., et al., Proc. Am. Assoc. Cancer Res.,1998, 39, 89 Meet., 384). PKC β inhibitors (by blocking the MAP kinasesignal transduction pathways for VEGF (Vascular Endothelial GrowthFactor) and bFGF (basic Fibrinogen Growth Factor) in endothelial cells),in a combination regimen with other anti-cancer agents, have ananti-angiogenic and antitumor effect in a human T98G glioblastomamultiforme xenograft model (Teicher, B. A., et al., Clinical CancerResearch, 2001 (March), 7, 634-640). Accordingly, PKC inhibitors may beindicated for use in ameliorating angiogenesis and in treating orameliorating cancers (such as breast, brain, kidney, bladder, ovarian orcolon cancers) and as adjuncts to chemotherapy and radiation therapy.

Central Nervous System Disorders

PKC activity plays a central role in the functioning of the centralnervous system (CNS) (Huang, K. P., Trends Neurosci., 1989, 12, 425-432)and PKC is implicated in Alzheimer's disease (Shimohama, S., et al.,Neurology, 1993, 43, 1407-1413) and inhibitors have been shown toprevent the damage seen in focal and central ischemic brain injury andbrain edema (Hara, H., et al., J. Cereb. Blood Flow Metab., 1990, 10,646-653; Shibata, S., et al., Brain Res., 1992, 594, 290-294).Accordingly, PKC inhibitors may be indicated for use in treatingAlzheimer's disease and in treating neurotraumatic and ischemia-relateddiseases.

The long-term increase in PKC γ (as a component of the phosphoinositide2^(nd) messenger system) and muscarinic acetylcholine receptorexpression in an amygdala-kindled rat model has been associated withepilepsy, serving as a basis for the rat's permanent state ofhyperexcitability (Beldhuis, H. J. A., et al., Neuroscience, 1993, 55,4, 965-73). Therefore, PKC inhibitors may be indicated for use intreating epilepsy.

The subcellular changes in content of the PKC γ and PKC β-II isoenzymesfor animals in an in-vivo thermal hyperalgesia model suggests thatperipheral nerve injury contributes to the development of persistentpain (Miletic, V., et al., Neurosci. Lett., 2000, 288, 3, 199-202). Micelacking PKC γ display normal responses to acute pain stimuli, but almostcompletely fail to develop a neuropathic pain syndrome after partialsciatic nerve section (Chen, C., et al., Science (Wash., D.C.), 1997,278, 5336, 279-283). PKC modulation may thus be indicated for use intreating chronic pain and neuropathic pain.

PKC has demonstrated a role in the pathology of conditions such as, butnot limited to, cardiovascular diseases, diabetes, diabetes-associateddisorders, inflammatory diseases, immunological disorders,dermatological disorders, oncological disorders and central nervoussystem disorders.

Glycogen Synthase Kinase-3

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinasecomposed of two isoforms (α and β) which are encoded by distinct genes.GSK-3 is one of several protein kinases which phosphorylate glycogensynthase (GS) (Embi, et al., Eur. J. Biochem, 1980, 107, 519-527). The αand β isoforms have a monomeric structure of 49 and 47 kD respectivelyand are both found in mammalian cells. Both isoforms phosphorylatemuscle glycogen synthase (Cross, et al., Biochemical Journal, 1994, 303,21-26) and these two isoforms show good homology between species (humanand rabbit GSK-3α are 96% identical).

Diabetes

Type II diabetes (or Non-insulin Dependent Diabetes Mellitus, NIDDM) isa multifactorial disease. Hyperglycemia is due to insulin resistance inthe liver, muscle and other tissues coupled with inadequate or defectivesecretion of insulin from pancreatic islets. Skeletal muscle is themajor site for insulin-stimulated glucose uptake and in this tissueglucose removed from the circulation is either metabolised throughglycolysis and the TCA (tricarboxylic acid) cycle or stored as glycogen.Muscle glycogen deposition plays the more important role in glucosehomeostasis and Type II diabetic subjects have defective muscle glycogenstorage. The stimulation of glycogen synthesis by insulin in skeletalmuscle results from the dephosphorylation and activation of glycogensynthase (Villar-Palasi C. and Larner J., Biochim. Biophys. Acta, 1960,39, 171-173, Parker P. J., et al., Eur. J. Biochem., 1983, 130, 227-234,and Cohen P., Biochem. Soc. Trans., 1993, 21, 555-567). Thephosphorylation and dephosphorylation of GS are mediated by specifickinases and phosphatases. GSK-3 is responsible for phosphorylation anddeactivation of GS, while glycogen bound protein phosphatase 1 (PP1G)dephosphorylates and activates GS. Insulin both inactivates GSK-3 andactivates PP1G (Srivastava A. K. and Pandey S. K., Mol. and CellularBiochem., 1998, 182, 135-141).

Studies suggest that an increase in GSK-3 activity might be important inType II diabetic muscle (Chen, et al., Diabetes, 1994, 43, 1234-1241).Overexpression of GSK-3, and constitutively active GSK-3, (S9A, S9e)mutants in HEK-293 cells resulted in suppression of glycogen synthaseactivity (Eldar-Finkelman, et al., PNAS, 1996, 93, 10228-10233) andoverexpression of GSK-3, in CHO cells, expressing both insulin receptorand insulin receptor substrate 1 (IRS-1) resulted in impairment ofinsulin action (Eldar-Finkelman and Krebs, PNAS, 1997, 94, 9660-9664).Recent evidence for the involvement of elevated GSK-3 activity and thedevelopment of insulin resistance and Type II diabetes in adipose tissuehas emerged from studies undertaken in diabetes and obesity proneC57BL/6J mice (Eldar-Finkelman, et al., Diabetes, 1999, 48, 1662-1666).

Dermatological Disorders

The finding that transient β-catenin stabilization may play a role inhair development (Gat, et al., Cell, 1998, 95, 605-614) suggests thatGSK-3 inhibitors could also be used in the treatment of baldness.

Inflammatory Diseases

Studies on fibroblasts from the GSK-3β knockout mouse indicate thatinhibition of GSK-3 may be useful in treating inflammatory disorders ordiseases through the negative regulation of NFkB activity (Hoeflich K.P., et al., Nature, 2000, 406, 86-90).

Central Nervous System Disorders

In addition to modulation of glycogen synthase activity, GSK-3 alsoplays an important role in the CNS disorders. GSK-3 inhibitors may be ofvalue as neuroprotectants in the treatment of acute stroke and otherneurotraumatic injuries (Pap and Cooper, J. Biol. Chem., 1998, 273,19929-19932). Lithium, a low mM inhibitor of GSK-3, has been shown toprotect cerebellar granule neurons from death (D'Mello, et al., Exp.Cell Res., 1994, 211, 332-338) and chronic lithium treatment hasdemonstrable efficacy in the middle cerebral artery occlusion model ofstroke in rodents (Nonaka and Chuang, Neuroreport, 1998, 9(9),2081-2084).

Tau and β-catenin, two known in vivo substrates of GSK-3, are of directrelevance in consideration of further aspects of the value of GSK-3inhibitors in relation to treatment of chronic neurodegenerativeconditions. Tau hyperphosphorylation is an early event inneurodegenerative conditions such as Alzheimer's disease and ispostulated to promote microtubule disassembly. Lithium has been reportedto reduce the phosphorylation of tau, enhance the binding of tau tomicrotubules and promote microtubule assembly through direct andreversible inhibition of GSK-3 (Hong M. et al J. Biol. Chem., 1997,272(40), 25326-32). β-catenin is phosphorylated by GSK-3 as part of atripartite axin protein complex resulting in β-catenin degradation(Ikeda, et al., EMBO J., 1998, 17, 1371-1384). Inhibition of GSK-3activity is involved in the stabilization of catenin hence promotesβ-catenin-LEF-1/TCF transcriptional activity (Eastman, Grosschedl, Curr.Opin. Cell Biol., 1999, 11, 233). Studies have also suggested that GSK-3inhibitors may also be of value in treatment of schizophrenia (CotterD., et al. Neuroreport, 1998, 9, 1379-1383; Lijam N., et al., Cell,1997, 90, 895-905) and manic depression (Manji, et al., J. Clin.Psychiatry, 1999, 60, (Suppl 2) 27-39 for review).

Accordingly, compounds found useful as GSK-3 inhibitors could havefurther therapeutic utility in the treatment of diabetes, dermatologicaldisorders, inflammatory diseases and central nervous system disorders.

Embodiments of the method of the present invention include a method fortreating or ameliorating a kinase or dual-kinase mediated disorder in asubject in need thereof comprising administering to the subject atherapeutically effective amount of an instant compound orpharmaceutical composition thereof. The therapeutically effective amountof the compounds of Formula (I) exemplified in such a method is fromabout 0.001 mg/kg/day to about 300 mg/kg/day.

Embodiments of the present invention include the use of a compound ofFormula (I) for the preparation of a medicament for treating orameliorating a kinase or dual-kinase mediated disorder in a subject inneed thereof.

In accordance with the methods of the present invention, an individualcompound of the present invention or a pharmaceutical compositionthereof can be administered separately at different times during thecourse of therapy or concurrently in divided or single combinationforms. The instant invention is therefore to be understood as embracingall such regimes of simultaneous or alternating treatment and the term“administering” is to be interpreted accordingly.

Embodiments of the present method include a compound or pharmaceuticalcomposition thereof advantageously co-administered in combination withother agents for treating or ameliorating a kinase or dual-kinasemediated disorder. For example, in the treatment of diabetes, especiallyType II diabetes, a compound of Formula (I) or pharmaceuticalcomposition thereof may be used in combination with other agents,especially insulin or antidiabetic agents including, but not limited to,insulin secretagogues (such as sulphonylureas), insulin sensitizersincluding, but not limited to, glitazone insulin sensitizers (such asthiazolidinediones) or biguanides or a glucosidase inhibitors.

The combination product comprises co-administration of a compound ofFormula (I) or pharmaceutical composition thereof and an additionalagent for treating or ameliorating a kinase or dual-kinase mediateddisorder, the sequential administration of a compound of Formula (I) orpharmaceutical composition thereof and an additional agent for treatingor ameliorating a kinase or dual-kinase mediated disorder,administration of a pharmaceutical composition containing a compound ofFormula (I) or pharmaceutical composition thereof and an additionalagent for treating or ameliorating a kinase or dual-kinase mediateddisorder or the essentially simultaneous administration of a separatepharmaceutical composition containing a compound of Formula (I) orpharmaceutical composition thereof and a separate pharmaceuticalcomposition containing an additional agent for treating or amelioratinga kinase or dual-kinase mediated disorder.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or human,that is being sought by a researcher, veterinarian, medical doctor, orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

The ubiquitous nature of the PKC and GSK isoforms and their importantroles in physiology provide incentive to produce highly selective PKCand GSK inhibitors. Given the evidence demonstrating linkage of certainisoforms to disease states, it is reasonable to assume that inhibitorycompounds that are selective to one or two PKC isoforms or to a GSKisoform relative to the other PKC and GSK isoforms and other proteinkinases are superior therapeutic agents. Such compounds shoulddemonstrate greater efficacy and lower toxicity by virtue of theirspecificity. Accordingly, it will be appreciated by one skilled in theart that a compound of Formula (I) is therapeutically effective forcertain kinase or dual-kinase mediated disorders based on the modulationof the disorder by selective kinase or dual-kinase inhibition. Theusefulness of a compound of Formula (I) as a selective kinase ordual-kinase inhibitor can be determined according to the methodsdisclosed herein and the scope of such use includes use in one or morekinase or dual-kinase mediated disorders.

Therefore, the term “kinase or dual-kinase mediated disorders” as usedherein, includes, and is not limited to, cardiovascular diseases,diabetes, diabetes-associated disorders, inflammatory diseases,immunological disorders, dermatological disorders, oncological disordersand CNS disorders.

Cardiovascular diseases include, and are not limited to, acute stroke,heart failure, cardiovascular ischemia, thrombosis, atherosclerosis,hypertension, restenosis, retinopathy of prematurity or age-relatedmacular degeneration. Diabetes includes insulin dependent diabetes orType II non-insulin dependent diabetes mellitus. Diabetes-associateddisorders include, and are not limited to, impaired glucose tolerance,diabetic retinopathy, proliferative retinopathy, retinal vein occlusion,macular edema, cardiomyopathy, nephropathy or neuropathy. Inflammatorydiseases include, and are not limited to, vascular permeability,inflammation, asthma, rheumatoid arthritis or osteoarthritis.Immunological disorders include, and are not limited to, transplanttissue rejection, HIV-1 or immunological disorders treated orameliorated by PKC modulation. Dermatological disorders include, and arenot limited to, psoriasis, hair loss or baldness. Oncological disordersinclude, and are not limited to, cancers or tumor growth (such asbreast, brain, kidney, bladder, ovarian or colon cancer or leukemia),proliferative angiopathy and angiogenesis; and, includes use forcompounds of Formula (I) as an adjunct to chemotherapy and radiationtherapy. CNS disorders include, and are not limited to, chronic pain,neuropathic pain, epilepsy, chronic neurodegenerative conditions (suchas dementia or Alzheimer's disease), mood disorders (such asschizophrenia), manic depression or neurotraumatic, cognitive declineand ischemia-related diseases {as a result of head trauma (from acuteischemic stroke, injury or surgery) or transient ischemic stroke (fromcoronary bypass surgery or other transient ischemic conditions)}.

In another embodiment of a method of treating or ameliorating a disorderselected from the group consisting of diabetes-associated disorders,dermatological disorders, oncological disorders and central nervoussystem disorders comprising administering to a subject in need oftreatment a therapeutically effective amount of a compound of Formula(I):

wherein

-   R¹ and R² are independently selected from the group consisting of:-   hydrogen,-   C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl {wherein alkyl, alkenyl and    alkynyl are optionally substituted with one to two substituents    independently selected from the group consisting of —O—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-OH, —O—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-NH₂,    —O—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,    —O—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-SO₂—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-SO₂—NH₂, —O—(C₁₋₈)alkyl-SO₂—NH—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-SO₂—N[(C₁₋₈)alkyl]₂, —O—C(O)H, —O—C(O)—(C₁₋₈)alkyl,    —O—C(O)—NH₂, —O—C(O)—NH—(C₁₋₈)alkyl, O—C(O)—N[(C₁₋₈)alkyl]₂,    —O—(C₁₋₈)alkyl-C(O)H, —O—(C₁₋₈)alkyl-C(O)—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-CO₂H, —O—(C₁₋₈)alkyl-C(O)—O—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-C(O)—NH₂, —O—(C₁₋₈)alkyl-C(O)—NH—(C₁₋₈)alkyl,    —O—(C₁₋₈)alkyl-C(O)—N[(C₁₋₈)alkyl]₂, —C(O)H, —C(O)—(C₁₋₈)alkyl,    —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SH, —S—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-OH, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH₂,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl,    —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,    —S—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,    —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-OH,    —(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-NH₂,    —(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,    —(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl,    —C(O)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂,    —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl,    —SO₂—N[(C₁₋₈)alkyl]₂, —C(N)—NH₂, aryl and aryl(C₁₋₈)alkyl (wherein    aryl is optionally substituted with one to three substituents    independently selected from the group consisting of halogen,    C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted with two substituents    selected from the group consisting of hydrogen and C₁₋₈alkyl),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkoxy, hydroxy,    hydroxy(C₁₋₈)alkyl and nitro)), cyano, (halo)₁₋₃, hydroxy, nitro,    oxo, heterocyclyl, aryl and heteroaryl (wherein heterocyclyl, aryl    and heteroaryl are optionally substituted with one to three    substituents independently selected from the group consisting of    C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted with two substituents    selected from the group consisting of hydrogen and C₁₋₈alkyl),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkoxy, hydroxy,    hydroxy(C₁₋₈)alkyl and nitro)},-   —C(O)—(C₁₋₈)alkyl, —C(O)-aryl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—O-aryl,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—NH-aryl, —C(O)—N[(C₁₋₈)alkyl]₂,    —SO₂—(C₁₋₈)alkyl, —SO₂-aryl,-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to three substituents independently selected    from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,    C₁₋₈alkoxy, —C(O)H, —C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl,    —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂,    —SH, —S—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,    —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with    two substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    amino-(C₁₋₈)alkyl- (wherein amino is substituted with two    substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl-, (halo)₁₋₃(C₁₋₈)alkoxy-, hydroxy,    hydroxy(C₁₋₈)alkyl, nitro, aryl, —(C₁₋₈)alkyl-aryl, heteroaryl and    —(C₁₋₈)alkyl-heteroaryl};-   X is selected from the group consisting of N and CR⁵;-   R³ and R⁴ are independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, —C(O)H,    —C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(NH)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SH,    —S—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl,    —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with two substituents    independently selected from the group consisting of hydrogen,    C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    amino-(C₁₋₈)alkyl- (wherein amino is substituted with two    substituents independently selected from the group consisting of    hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,    —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,    —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₁₈)alkyl,    —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),    cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl-, (halo)₁₋₃(C₁₋₈)alkoxy-, hydroxy,    hydroxy(C₁₋₈)alkyl-, nitro, aryl, —(C₁₋₈)alkyl-aryl, heteroaryl and    —(C₁₋₈)alkyl-heteroaryl;-   Y and Z are independently selected from the group consisting of O,    S, (H,OH) and (H,H); with the proviso that one of Y and Z is O and    the other is selected from the group consisting of O, S, (H,OH) and    (H,H); and,-   R⁵ is selected from the group consisting of:-   hydrogen, halogen,-   C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl {wherein alkyl, alkenyl and    alkynyl are optionally substituted with one to two substituents    independently selected from the group consisting of amino    (substituted with two substituents selected from the group    consisting of hydrogen and C₁₋₈alkyl), cyano, halo, hydroxy, nitro,    oxo, aryl and heteroaryl},-   aryl and heteroaryl {wherein aryl and heteroaryl are optionally    substituted with one to two substituents independently selected from    the group consisting of C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted    with two substituents selected from the group consisting of hydrogen    and C₁₋₈alkyl), cyano, halo, hydroxy and nitro};    and pharmaceutically acceptable salts thereof.

A compound may be administered to a subject in need of treatment by anyconventional route of administration including, but not limited to oral,nasal, sublingual, ocular, transdermal, rectal, vaginal and parenteral(i.e. subcutaneous, intramuscular, intradermal, intravenous etc.).

To prepare the pharmaceutical compositions of this invention, one ormore compounds of Formula (I) or salt thereof as the active ingredient,is intimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration (e.g. oral or parenteral). Suitablepharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman,et al.; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes1-2, edited by Avis, et al.; and Pharmaceutical Dosage Forms: DisperseSystems, Volumes 1-2, edited by Lieberman, et al.; published by MarcelDekker, Inc.

In preparing a pharmaceutical composition of the present invention inliquid dosage form for oral, topical and parenteral administration, anyof the usual pharmaceutical media or excipients may be employed. Thus,for liquid dosage forms, such as suspensions (i.e. colloids, emulsionsand dispersions) and solutions, suitable carriers and additives includebut are not limited to pharmaceutically acceptable wetting agents,dispersants, flocculation agents, thickeners, pH control agents (i.e.buffers), osmotic agents, coloring agents, flavors, fragrances,preservatives (i.e. to control microbial growth, etc.) and a liquidvehicle may be employed. Not all of the components listed above will berequired for each liquid dosage form.

In solid oral preparations such as, for example, powders, granules,capsules, caplets, gelcaps, pills and tablets (each including immediaterelease, timed release and sustained release formulations), suitablecarriers and additives include but are not limited to diluents,granulating agents, lubricants, binders, glidants, disintegrating agentsand the like. Because of their ease of administration, tablets andcapsules represent the most advantageous oral dosage unit form, in whichcase solid pharmaceutical carriers are obviously employed. If desired,tablets may be sugar coated, gelatin coated, film coated or entericcoated by standard techniques.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder, injection, teaspoonful and the like, anamount of the active ingredient necessary to deliver an effective doseas described above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.001 mg to about300 mg (preferably, from about 0.01 mg to about 100 mg; and, morepreferably, from about 0.1 mg to about 30 mg) and may be given at adosage of from about 0.001 mg/kg/day to about 300 mg/kg/day (preferably,from about 0.01 mg/kg/day to about 100 mg/kg/day; and, more preferably,from about 0.1 mg/kg/day to about 30 mg/kg/day). Preferably, in themethod for treating or ameliorating a kinase or dual-kinase mediateddisorder described in the present invention and using any of thecompounds as defined herein, the dosage form will contain apharmaceutically acceptable carrier containing between about 0.01 mg and100 mg; and, more preferably, between about 5 mg and 50 mg of thecompound; and, may be constituted into any form suitable for the mode ofadministration selected. The dosages, however, may be varied dependingupon the requirement of the subjects, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, lozenges, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories for administration byoral, intranasal, sublingual, intraocular, transdermal, parenteral,rectal, vaginal, inhalation or insufflation means. Alternatively, thecomposition may be presented in a form suitable for once-weekly oronce-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection.

For preparing solid pharmaceutical compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as diluents, binders, adhesives,disintegrants, lubricants, antiadherents and glidants. Suitable diluentsinclude, but are not limited to, starch (i.e. corn, wheat, or potatostarch, which may be hydrolized), lactose (granulated, spray dried oranhydrous), sucrose, sucrose-based diluents (confectioner's sugar;sucrose plus about 7 to 10 weight percent invert sugar; sucrose plusabout 3 weight percent modified dextrins; sucrose plus invert sugar,about 4 weight percent invert sugar, about 0.1 to 0.2 weight percentcornstarch and magnesium stearate), dextrose, inositol, mannitol,sorbitol, microcrystalline cellulose (i.e. AVICEL™ microcrystallinecellulose available from FMC Corp.), dicalcium phosphate, calciumsulfate dihydrate, calcium lactate trihydrate and the like. Suitablebinders and adhesives include, but are not limited to acacia gum, guargum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics(i.e. methylcellulose, sodium carboxymethycellulose, ethylcellulose,hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like),water soluble or dispersible binders (i.e. alginic acid and saltsthereof, magnesium aluminum silicate, hydroxyethylcellulose (i.e.TYLOSE™ available from Hoechst Celanese), polyethylene glycol,polysaccharide acids, bentonites, polyvinylpyrrolidone,polymethacrylates and pregelatinized starch) and the like. Suitabledisintegrants include, but are not limited to, starches (corn, potato,etc.), sodium starch glycolates, pregelatinized starches, clays(magnesium aluminum silicate), celluloses (such as crosslinked sodiumcarboxymethylcellulose and microcrystalline cellulose), alginates,pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar,locust bean, karaya, pectin and tragacanth gum), cross-linkedpolyvinylpyrrolidone and the like. Suitable lubricants and antiadherentsinclude, but are not limited to, stearates (magnesium, calcium andsodium), stearic acid, talc waxes, stearowet, boric acid, sodiumchloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate,sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium laurylsulfate and the like. Suitable glidants include, but are not limited to,talc, cornstarch, silica (i.e. CAB-O-SIL™ silica available from Cabot,SYLOID™ silica available from W.R. Grace/Davison and AEROSIL™ silicaavailable from Degussa) and the like. Sweeteners and flavorants may beadded to chewable solid dosage forms to improve the palatability of theoral dosage form. Additionally, colorants and coatings may be added orapplied to the solid dosage form for ease of identification of the drugor for aesthetic purposes. These carriers are formulated with thepharmaceutical active to provide an accurate, appropriate dose of thepharmaceutical active with a therapeutic release profile.

Generally these carriers are mixed with the pharmaceutical active toform a solid preformulation composition containing a homogeneous mixtureof the pharmaceutical active of the present invention, or apharmaceutically acceptable salt thereof. Generally the preformulationwill be formed by one of three common methods: (a) wet granulation, (b)dry granulation and (c) dry blending. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing from about 0.1 mg to about 500 mg of theactive ingredient of the present invention. The tablets or pillscontaining the novel compositions may also be formulated in multilayertablets or pills to provide a sustained or provide dual-releaseproducts. For example, a dual release tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer, which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric materials such as shellac, cellulose acetate (i.e. celluloseacetate phthalate), polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, methacrylate and ethylacrylate copolymers, methacrylate andmethyl methacrylate copolymers and the like. Sustained release tabletsmay also be made by film coating or wet granulation using slightlysoluble or insoluble substances in solution (which for a wet granulationacts as the binding agents) or low melting solids a molten form (whichin a wet granulation may incorporate the active ingredient). Thesematerials include natural and synthetic polymers waxes, hydrogenatedoils, fatty acids and alcohols (i.e. beeswax, carnauba wax, cetylalcohol, cetylstearyl alcohol and the like), esters of fatty acidsmetallic soaps and other acceptable materials that can be used togranulate, coat, entrap or otherwise limit the solubility of an activeingredient to achieve a prolonged or sustained release product.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, but are not limited to aqueous solutions, suitably flavoredsyrups, aqueous or oil suspensions and flavored emulsions with edibleoils such as cottonseed oil, sesame oil, coconut oil or peanut oil, aswell as elixirs and similar pharmaceutical vehicles. Suitable suspendingagents for aqueous suspensions, include synthetic and natural gums suchas, acacia, agar, alginate (i.e. propylene alginate, sodium alginate andthe like), guar, karaya, locust bean, pectin, tragacanth and xanthangum, cellulosics such as sodium carboxymethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl celluloseand hydroxypropyl methylcellulose and combinations thereof, syntheticpolymers such as polyvinyl pyrrolidone, carbomer (i.e.carboxypolymethylene) and polyethylene glycol; clays such as bentonite,hectorite, attapulgite or sepiolite; and other pharmaceuticallyacceptable suspending agents such as lecithin, gelatin or the like.Suitable surfactants include but are not limited to sodium docusate,sodium lauryl sulfate, polysorbate, octoxynol-9, nonoxynol-10,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80,polyoxamer 188, polyoxamer 235 and combinations thereof. Suitabledeflocculating or dispersing agent include pharmaceutical gradelecithins. Suitable flocculating agent include but are not limited tosimple neutral electrolytes (i.e. sodium chloride, potassium, chlorideand the like), highly charged insoluble polymers and polyelectrolytespecies, water soluble divalent or trivalent ions (i.e. calcium salts,alums or sulfates, citrates and phosphates (which can be used jointly informulations as pH buffers and flocculating agents). Suitablepreservatives include but are not limited to parabens (i.e. methyl,ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, quaternaryammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate,phenylethanol and the like. There are many liquid vehicles that may beused in liquid pharmaceutical dosage forms, however, the liquid vehiclethat is used in a particular dosage form must be compatible with thesuspending agent(s). For example, nonpolar liquid vehicles such as fattyesters and oils liquid vehicles are best used with suspending agentssuch as low HLB (Hydrophile-Lipophile Balance) surfactants,stearalkonium hectorite, water insoluble resins, water insoluble filmforming polymers and the like. Conversely, polar liquids such as water,alcohols, polyols and glycols are best used with suspending agents suchas higher HLB surfactants, clays silicates, gums, water solublecellulosics, water soluble polymers and the like. For parenteraladministration, sterile suspensions and solutions are desired. Liquidforms useful for parenteral administration include sterile solutions,emulsions and suspensions. Isotonic preparations which generally containsuitable preservatives are employed when intravenous administration isdesired.

Furthermore, compounds of the present invention can be administered inan intranasal dosage form via topical use of suitable intranasalvehicles or via transdermal skin patches, the composition of which arewell known to those of ordinary skill in that art. To be administered inthe form of a transdermal delivery system, the administration of atherapeutic dose will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Compounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, multilamellar vesicles and the like. Liposomes canbe formed from a variety of phospholipids, such as cholesterol,stearylamine, phosphatidylcholines and the like.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include, but are not limited to polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example, tohomopolymers and copolymers (which means polymers containing two or morechemically distinguishable repeating units) of lactide (which includeslactic acid d-, l- and meso lactide), glycolide (including glycolicacid), ε-caprolactone, p-dioxanone (1,4-dioxan-2-one), trimethylenecarbonate (1,3-dioxan-2-one), alkyl derivatives of trimethylenecarbonate, δ-valerolactone, β-butyrolactone, γ-butyrolactone,ε-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxepan-2-one(including its dimer 1,5,8,12-tetraoxacyclotetradecane-7,14-dione),1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels and blends thereof.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever treating or amelioratinga kinase or dual-kinase mediated disorder is required for a subject inneed thereof; in particular, whenever treating or ameliorating a kinasedisorder mediated by selective inhibition of a kinase selected fromprotein kinase C or glycogen synthase kinase-3 is required; and,whenever treating or ameliorating a kinase disorder mediated by dualinhibition of at least two kinases selected from protein kinase C andglycogen synthase kinase-3 is required; and, more particularly, whenevertreating or ameliorating a kinase disorder mediated by selectiveinhibition of a kinase selected from protein kinase C α, protein kinaseC β-II, protein kinase C γ or glycogen synthase kinase-3β is required;and, whenever treating or ameliorating a kinase disorder mediated bydual inhibition of at least two kinases selected from protein kinase Cα, protein kinase C β-II, protein kinase C γ or glycogen synthasekinase-3β is required.

The daily dose of a pharmaceutical composition of the present inventionmay be varied over a wide range from about 0.7 mg to about 21,000 mg per70 kilogram (kg) adult human per day; preferably in the range of fromabout 7 mg to about 7,000 mg per adult human per day; and, morepreferably, in the range of from about 7 mg to about 2,100 mg per adulthuman per day. For oral administration, the compositions are preferablyprovided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe subject to be treated. A therapeutically effective amount of thedrug is ordinarily supplied at a dosage level of from about 0.001 mg/kgto about 300 mg/kg of body weight per day. Preferably, the range is fromabout 0.1 mg/kg to about 100 mg/kg of body weight per day; and, mostpreferably, from about 0.1 mg/kg to about 30 mg/kg of body weight perday. Advantageously, compounds of the present invention may beadministered in a single daily dose or the total daily dosage may beadministered in divided doses of two, three or four times daily.

Optimal dosages to be administered may be readily determined by thoseskilled in the art and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular subject being treated, including subject age,weight, diet and time of administration, will result in the need toadjust the dose to an appropriate therapeutic level.

Abbreviations used in the instant specification, particularly theSchemes and Examples, are as follows:

ATP = adenosinetriphosphate BSA = bovine serum albumin DCM =dichloromethane DMF = N,N-dimethylformamide DMSO = dimethylsulfoxideEDTA = ethylenediaminetetraacetic acid EGTA =ethylenebis(oxyethylenenitrilo)tetraacetic acid h = hour HEPES =4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid min = minute rt =room temperature TCA = trichloroacetic acid THF = tetrahydrofuran TFA =trifluoroacetic acid TMSCHN₂ = trimethylsilyldiazomethane

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated more particularly in the schemes that follow. Since theschemes are an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

The following schemes describe general synthetic methods wherebyintermediate and target compounds of the present invention may beprepared. Additional representative compounds of the present inventioncan be synthesized using the intermediates prepared in accordance withthe schemes and other materials, compounds and reagents known to thoseskilled in the art.

In Scheme AA, the substituted indole Compound AA1 was arylated with anappropriately substituted aryl or heteroaryl halide and a base such ascesium or potassium carbonate and copper oxide in a dipolar aproticsolvent such as DMF to give Compound AA2. Compound AA2 was acylated withoxalyl chloride in an aprotic solvent such as diethyl ether or DCM andquenched with sodium methoxide to afford an intermediate glyoxylic esterCompound AA3.

Another intermediate Compound AA5 was prepared from Compound AA1 viaacylation with oxalyl chloride followed by treatment with sodiummethoxide to afford glyoxylic ester Compound AA4 which was thenalkylated with 1,2-dibromoethane under basic conditions to deriveCompound AA5.

The intermediate Compound AA6 was prepared from Compound AA4 viaalkylation with an appropriate alkylating agent under basic conditions.

The substituted 3-indazoleacetic acid Compound AA8 was prepared fromaldehyde Compound AA7 by reaction with malonic acid and ammonium formatefollowed by reductive cyclization under basic conditions (B. Mylari, etal., J. Med. Chem., 1992, 35, 2155). The acid Compound AA8 was coupledwith ammonium hydroxide in an aprotic solvent such as DCM oracetonitrile using a dehydrating agent like dicyclohexyl carbodiimide(DCC) and 1-hydroxybenzotriazole (HOBT) to give amide Compound AA9,which was treated with an appropriate alkylating agent in the presenceof a base such as sodium hydride to afford indazole Compound AA10 as amixture of N1-alkylated (major) and N2-alkylated (minor) products.

Target Compound AA11, having a variety of R¹ and R² substituents, may beprepared using Compound AA3, Compound AA5 or Compound AA6 in reactionwith the amide Compound AA10.

The ester Compound AA3 (wherein R¹ is an aryl or heteroaryl) may bereacted with the amide Compound AA10 stirred in an aprotic solvent suchas THF with ice bath cooling and a base, such as potassium tert-butoxideor sodium hydride, to give a target Compound AA11. Alternatively, theester Compound AA5 may be condensed with Compound AA10 under strongbasic conditions, concomitantly causing the elimination of HBr, to givea target Compound AA11 (wherein R¹ is vinyl) as the product. Also, theester Compound AA6 (wherein R¹ is selected from alkyl, arylalkyl,heteroarylalkyl, alkoxyalkyl, dialkylaminoalkyl, etc.) may reacted withCompound AA10 under basic conditions to give a target Compound AA11 asthe product.

Specific Synthetic Methods

Specific compounds which are representative of this invention wereprepared as per the following examples and reaction sequences; theexamples and the diagrams depicting the reaction sequences are offeredby way of illustration, to aid in the understanding of the invention andshould not be construed to limit in any way the invention set forth inthe claims which follow thereafter. The depicted intermediates may alsobe used in subsequent examples to produce additional compounds of thepresent invention. No attempt has been made to optimize the yieldsobtained in any of the reactions. One skilled in the art would know howto increase such yields through routine variations in reaction times,temperatures, solvents and/or reagents.

All chemicals were obtained from commercial suppliers and used withoutfurther purification. ¹H and ¹³C NMR spectra were recorded on a BrukerAC 300B (300 MHz proton) or a Bruker AM-400 (400 MHz proton)spectrometer with Me₄Si as an internal standard (s=singlet, d=doublet,t=triplet, br=broad). APCI-MS and ES-MS were recorded on a VG PlatformII mass spectrometer; methane was used for chemical ionization, unlessnoted otherwise. Accurate mass measurements were obtained by using a VGZAB 2-SE spectrometer in the FAB mode. TLC was performed with Whatman250-μm silica gel plates. Preparative TLC was performed with Analtech1000-μm silica gel GF plates. Flash column chromatography was conductedwith flash column silica gel (40-63 μm) and column chromatography wasconducted with standard silica gel. HPLC separations were carried out onthree Waters PrepPak® Cartridges (25×100 mm, Bondapak® C18, 15-20 μm,125 Å) connected in series; detection was at 254 nm on a Waters 486 UVdetector. Analytical HPLC was carried out on a Supelcosil ABZ+PLUScolumn (5 cm×2.1 mm), with detection at 254 nm on a Hewlett Packard 1100UV detector. Microanalysis was performed by Robertson MicrolitLaboratories, Inc.

Representative Chemical Abstracts Service (CAS) Index-like names for thecompounds of the present invention were derived using the ACD/LABSSOFTWARE™ Index Name Pro Version 4.5 nomenclature software programprovided by Advanced Chemistry Development, Inc., Toronto, Ontario,Canada.

EXAMPLE 13-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-H-pyrrole-2,5-dione(Compound 12)

Indole Compound 1a (2.34 g, 20 mmol) and 3-bromopyridine (3.16 g, 20mmol) were dissolved in DMF (10 mL) and potassium carbonate (2.76 g, 20mmol). CuO (130 mg, 1.6 mmol) was added and the reaction was refluxedunder argon for 16 h. The reaction was cooled to rt and partitionedbetween DCM (100 mL) and water (100 mL). The organic layer was washedwith water (3×50 mL) and brine (2×50 mL), then dried (Na₂SO₄) andevaporated in vacuo to a brown oil. The product was purified via flashcolumn chromatography (ethyl acetate:hexane; 1:1) to give Compound 1b(3.16 g, 81%) as a colorless oil. The indole Compound 1b (0.78 g, 4.0mmol) in DCM (12 mL) was treated with oxalyl chloride (0.52 g, 4.1 mmol)with ice bath cooling and then stirred at ambient temperature for 16 h.The solution was cooled to −65° C. and sodium methoxide (0.46 g, 8.0mmol) in methanol (10 mL) was added slowly; the reaction was stirred atambient temperature for 1 h and then evaporated in vacuo to a solid. Thesolid was extracted with chloroform (25 mL), filtered and the filtratedried (K₂CO₃) and evaporated in vacuo to provide Compound 1c (0.73 g,65%) as a grey solid. ¹H NMR (CDCl₃) δ 8.88 (d, J=2.3 Hz, 1H), 8.77 (dd,J=4.7, 1.3 Hz, 1H), 8.60 (s, 1H), 8.54 (d, J=7.1 Hz, 1H), 7.90 (m, 1H),7.56 (m, 1H), 7.43 (m, 3H), 3.98 (s, 3H). ES-MS m/z 281 (MH⁺).

Using the procedure described for preparing Compound 2e (see Example 2),acid Compound 1d (5.28 g, 30 mmol) was dissolved in DCM (120 mL) and DMF(30 mL) under argon. HOBT (4.45 g, 33 mmol) and DCC (6.51 g, 32 mmol)were added and the reaction was stirred at ambient temperature for 1 h.Ammonium hydroxide (28%, 2.7 g, 44 mmol) was added over 5 min and thereaction was then stirred at ambient temperature for 16 h. A white solidwas filtered off. The filtrate was diluted with DCM (150 mL) andfiltered again. The DCM solution was extracted four times with 5% NaHCO₃(150 mL). The combined aqueous solution was treated with sodium chloride(190 g) and extracted with ethyl acetate (6×300 mL). The organic extractwas dried (Na₂SO₄) and evaporated in vacuo to a solid (6.25 g), whichwas triturated with diethyl ether (100 mL) and filtered to affordCompound 1e (3.52 g, 67%) as a white solid.

Indazole Compound 1e (2.62 g, 15 mmol) in DMF (35 mL) was combined with3-dimethylaminopropylchloride hydrochloride (2.61 g, 16.5 mmol) andcooled in an ice bath as 95% sodium hydride (0.80 g, 31.5 mmol) wasadded portionwise over a 20 min period. The reaction was stirred atambient temperature for 10 min and then placed in an oilbath at 55° C.for 3 h. After cooling to rt, the reaction was diluted with DCM (200 mL)and washed with 0.3N NaOH (200 mL), water (2×100 mL) and brine (50 mL),then dried (K₂CO₃) and evaporated in vacuo to a first crop of lightyellow solid (2.50 g). The aqueous solutions were re-extracted with DCM(3×100 mL) and the DCM was washed with brine, then dried (K₂CO₃) andevaporated in vacuo to give a second crop (1.63 g). These two crops werecombined and purified by flash column chromatography (DCM:MeOH:NH₄OH;90:9:1) to afford Compound 1f (2.63 g, 64%) as a white solid.

The ester Compound 1c (700 mg, 2.5 mmol) and amide Compound 1f (546 mg,2.1 mmol) were combined in dry THF (10 mL) under argon and cooled withan ice bath as 1 M potassium t-butoxide in THF (8.4 mL, 8.4 mmol) wasadded with stirring over a 20 min period. After 1 h, the reaction wasquenched in an ice bath, 12 N HCl (3.5 mL, 42 mmol) was slowly addedover a 3 min period. The mixture was stirred for 5 min and thenpartitioned between chloroform:2-propanol (10:1; 200 mL) and saturatedNaHCO₃. The organic solution was washed with brine, then dried (Na₂SO₄)and evaporated in vacuo to a flaky solid. The solid was then purified byflash column chromatography (90:9:1; DCM:MeOH:NH₄OH) to afford Compound12 (0.70 g, 68%) as an orange flaky solid. A portion of Compound 12 wasdissolved in excess dilute HCl, then frozen and lyophilized to give thehydrochloride salt. ¹H NMR (DMSO) δ 8.97 (s, 1H), 8.75 (bd s, 1H), 8.40(s, 1H), 8.27 (d, J=9.2 Hz, 1H), 7.78 (m, 3H), 7.51 (m, 2H), 7.18 (m,2H), 6.88 (dd, J=7.5, 7.7 Hz, 1H), 6.49 (d, J=8.0 Hz, 1H), 4.47 (m, 2H),2.94 (m, 2H), 2.58 (s, 6H), 2.01 (m, 2H). ES-MS m/z 491 (MH⁺). Anal.Calcd. for C₂₉H₂₆N₆O₂.2HCl.2.5H₂O (490.56/608.52): C, 57.24; H, 5.46; N,13.81; H₂O, 7.40. Found: C, 57.06; H, 5.26; N, 13.89; H₂O, 6.92.

Using the procedure of Example 1 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 83-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(3- 496thienyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 113-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(3- 480furanyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 133-[5-chloro-1-(3-pyridinyl)-1H-indol-3-yl]-4-[1-[3- 525(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 173-[2-(2-naphthalenyl)-1-(3-pyridinyl-1H-indol-3-yl]-4-[1-[3- 617(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 183-[6-chloro-1-(3-pyridinyl)-1H-indol-3-yl]-4-[1-[3- 525(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 193-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(3- 541quinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 213-[1-[3-(diethylamino)propyl]-1H-indazol-3-yl]-4-[1-(3- 569quinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 223-[1-[3-(4-morpholinyl)propyl]-1H-indazol-3-yl]-4-[1-(3- 583quinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 233-[2,5-dihydro-2,5-dioxo-4-[1-(3-quinolinyl)-1H-indol-3-yl]- 5121H-pyrrol-3-yl]-1H-indazole-1-propionaldehyde 243-[1-[2-(1,3-dioxolan-2-yl)ethyl]-1H-indazol-3-yl]-4-[1-(3- 556quinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 253-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[5- 521methoxy-1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 273-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(6- 505methyl-3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 313-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2- 491pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 323-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(4- 491pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 333-[5-chloro-1-(2-thienyl)-1H-indol-3-yl]-4-[1-[3- 530(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 353-[1-(5-bromo-2-pyridinyl)-1H-indol-3-yl]-4-[1-[3- 569(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 383-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indazol- 4143-yl)-1H-pyrrole-2,5-dione 623-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2,5- 519dimethyl-3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 633-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(6- 570methoxy-2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 643-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(6- 556hydroxy-2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 653-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(6- 541quinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 933-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[1-[4- 560(dimethylamino)butyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 973-[1-[4-(dimethylamino)butyl]-1H-indazol-3-yl]-4-[1-(2- 554naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1013-[1-[2-(dimethylamino)ethyl]-1H-indazol-3-yl]-4-[1-(2- 526naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1033-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[1-[2- 532(dimethylamino)ethyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 23-[5-chloro-1-[3-(dimethylamino)-2-hydroxypropyl]-1H-indazol-3-yl]-4-(1-ethenyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(Compound 4)

A suspension of 10.0 g (0.053 mole) of Compound 2a in adichloromethane:methanol 6:1 mixture (350 mL) was stirred and cooled inan ice bath while adding 79 mL of a 2.0 M solution of TMSCHN₂ in hexanedropwise over a 1 hr period. The mixture was allowed to warm to rt andstirring continued over night. The resulting light yellow solid wasfiltered and washed with ether to yield Compound 2b (7.5 g, 70%). ¹H NMR(DMSO-d₆) δ 12.5 (s, 1H), 8.45 (d, 1H), 8.2 (d, 1H), 7.55 (d, 1H), 7.3(m, 2H), 3.95 (s, 3H).

Compound 2b (4.0 g, 0.0197 mole) and 1,2-dibromoethane (18.5 g, 0.0985mole) were combined in anhydrous DMF (80 mL) and treated with cesiumcarbonate (12.8 g, 0.0394 mole). The mixture was stirred under anatmosphere of argon at rt for 1 h. The temperature was raised to 50° C.for 4 h, then the mixture was stirred at rt over night. The resultingwhite solids were removed by filtration. The filtrate was partitionedbetween 600 mL of ether and 300 mL of water. The organic layer waswashed with water (3×) and brine, then dried over anhydrous sodiumsulfate. The solvent was removed in vacuo and the resulting oily residuetriturated with hexane to give a crude solid product. The crude solidwas recrystallized from ethyl acetate/hexane and flash chromatographedon silica eluted with ethyl acetate/hexane to give Compound 2c (5.5 g,47%).

Compound 2d (48 g, 0.22 mole), ammonium acetate (25.4 g, 0.33 mole) andmalonic acid (22.9 g, 0.22 mole) in absolute ethanol (200 mL) wereheated to reflux for a period of 9 h while stirring under an atmosphereof argon. The hot suspension was filtered and the solids were washedwith ethanol followed by ether to give a tan solid (21.0 g, 0.086 mole).The tan solid was dissolved in 5% aqueous sodium hydroxide (125 mL) thentreated with hydrazine monohydrate (4.8 g, 0.095 mole). The resultingmixture was warmed to 80° C., Raney-Nickel (about 70 mg) was then addedcautiously to the hot solution in two portions while stirring. Thereaction mixture temperature rose to about 90° C. and gas evolution wasnoted. Heating was continued for another 20 min until the gas evolutionstopped and then the mixture cooled to rt. The solids were removed byfiltration and the filtrate adjusted to pH 2 with 6N hydrochloric acidto give a golden solid. The solid was filtered, washed with water andair dried to give Compound 2e (14.6 g, 81%) as a light tan solid. ¹H NMR(DMSO-d₆) δ 13.1 (s, 1H), 7.85 (s, 1H), 7.55 (d, 1H), 7.35 (d, 1H), 4.0(s, 2H). ES-MS m/z 211 (MH⁺).

A suspension of 25 g of “Rink resin” in a mixture of anhydrous DMF (120mL) and piperidine (30 g) was stirred at rt for 2 h. The deprotectedresin was washed sequentially with DMF, dichloromethane, methanol andDMF. The resulting resin was suspended in of DMF (150 mL) and treatedwith Compound 2e (4.41 g, 0.021 mole) followed with HOBT (3.54 g, 0.026mole) and DCC (5.36 g, 0.026 mole). The mixture was stirred at rt for 24hrs and the resin filtered and washed with DMF. The resin was suspendedin fresh DMF (150 mL) then treated again with Compound 2e (1.0 g, 0.0048mole), HOBT (0.88 g, 0.0066 mole) and DCC (1.34 g, 0.0065 mole) andstirred at rt over night under argon. The resulting resin was washed asbefore to produce the Resin 2f (26.3 g). ES-MS m/Z 210 (MH⁺) of TFAcleaved sample.

A suspension of Resin 2f (13 g) in DMF (100 mL) was treated withepichlorohydrin (6.0 g, 0.065 mole) and cesium carbonate (4.23 g, 0.046mole) and stirred under argon at 70° C. for 4 h, then at rt over night.The reaction mixture was filtered and the crude resin washedsequentially with DMF, water, methanol, dichloromethane and ether togive Resin 2g (12.7 g). ES-MS m/z 266 (MH⁺) of the TFA cleaved sample.

A suspension of Resin 2g (2.0 g) in a 3:1 mixture of ethanol and THF (12mL) was treated with a 2N solution of dimethylamine (4 mL) in THF andstirred at 50° C. under argon for 1.5 h, then stirred over night at rt.The resulting resin was washed successively with methanol,dichloromethane and ether to produce 2.2 g of resin. The resin wasstirred at rt for 1.5 h in a 3:7:0.5 mixture of TFA, dichloromethane andanisole (20 mL). The cleaved resin was filtered and washed with a 30%TFA solution in dichloromethane. The combined filtrates wereconcentrated in vacuo and the residue triturated with ether to givecrude Compound 2h (400 mg) as a hygroscopic solid. ES-MS m/z 311 (MH⁺).

Compound 2h (400 mg, ca. 0.9 mmol) and Compound 2c (418 mg, 1.35 mmol)were combined in anhydrous THF (3 mL) and the mixture was stirred underargon and cooled in an ice bath while treating dropwise with 5 mL of 1 Npotassium t-butoxide in THF. The mixture was stirred an additional 5 minin an ice bath, then at rt for three h. The mixture was diluted withethyl acetate (100 mL) and washed with 10% sodium carbonate solution (30mL) followed by a brine wash and drying over anhydrous sodium sulfate.The dried solution was filtered and concentrated in vacuo to give thecrude product as a bright orange glass. Purification by flash columnchromatography on silica (eluting with a 92:7:1 mixture ofDCM:methanol:ammonium hydroxide) gave Compound 4 (110 mg, 25%) as anorange solid. ¹H NMR (CDCl₃) δ 8.35 (s, 1H), 7.8 (s, 1H), 7.6-7.1 (m,6H), 6.8 (t, 1H), 6.35 (d, 1H), 5.45 (d, 1H), 5.0 (d, 1H), 4.3 (m, 3H),3.7 (m, 1H), 2.4-2.05 (m, 8H). ES-MS m/z 490 (MH⁺).

Using the procedure of Example 2 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 1 3-[1-[3-(dimethylamino)-2-hydroxypropyl]-1H-446 indazol-3-yl]-4-(1-ethenyl-1H-indol-3-yl)-1H- pyrrole-2,5-dione 23-(1-ethenyl-1H-indol-3-yl)-4-[1-[2-hydroxy- 4423-(methylamino)propyl]-1H-indazol-3-yl]-1H- pyrrole-2,5-dione

EXAMPLE 33-[5-chloro-1-[3-(dimethylamino)-2-hydroxypropyl]-1H-indazol-3-yl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(Compound 40)

Compound 2b (406 mg, 0.002 mole), iodomethane (1.4 g, 0.01 mole) andcesium carbonate (1.3 g, 0.004 mole) were combined in anhydrous DMF (5mL) and stirred at 30° C. for 4 h under an atmosphere of argon. Thereaction mixture was then partitioned with ether (300 mL) and water(3×50 mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give Compound 3a (434 mg, 100%) as an oilyproduct that crystallized upon standing. ¹H NMR (CDCl₃) δ 8.45 (m, 1H),8.35 (s, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 4.0 (s, 3H), 3.9 (s, 3H).

Compound 2h (300 mg, 0.0007 mole) and Compound 3a (230 mg, 0.0011 mole)were combined in anhydrous THF (3 mL). The mixture was cooled in an icebath and stirred under argon while adding a 1 N solution of potassiumt-butoxide (4.2 mL) in THF dropwise. The mixture was allowed to warm tort and stirred for 3 h. The mixture was then diluted with ethyl acetate(150 mL) and washed with a 15% sodium carbonate solution followed bybrine. The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo to give Compound 40 as a crude product. Compound40 was purified via flash column chromatography on silica (eluting witha 92:7:1 mixture of dichloromethane:methanol:ammonia) to give Compound40 (85 mg) as an orange glass. ES-MS m/z 478 (MH⁺). ¹H NMR (CDCl₃) δ8.15 (s, 1H), 7.75 (s, 1H), 7.55 (d, 1H), 7.45-7.3 (m, 3H), 7.15 (t,1H), 6.7 (t, 1H), 6.15 (d, 1H), 4.2 (q, 2H), 3.9 (s, 3H), 3.75 (m, 1H),2.3-2.2 (m, 2H), 2.15 (s, 3H), 2.1 (t, 2H). Anal. Calc'd forC₂₅H₂₄ClN₅O₃: C, 62.83; H, 5.06: N, 14.65. Found: C, 61.45; H, 5.13; N,14.75.

Using the procedure of Example 3 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 39 3-[1-[3-(dimethylamino)-2-hydroxypropyl]-1H-430 indazol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5- dione 413-[1-[3-(dimethylamino)-2-hydroxypropyl]-1H- 444indazol-3-yl]-4-(1-methyl-1H-indol-3-yl)-1H- pyrrole-2,5-dione

EXAMPLE 43-(5-chloro-1-ethenyl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 6)3-(5-chloro-1-ethenyl-1H-indol-3-yl)-4-[2-[2-(dimethylamino)ethyl]-2H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 29)

A 5-chloroindole Compound 4a (7.7 g, 0.057 mole) in ether (80 mL) wascooled in an ice bath and treated dropwise with oxalyl chloride (6.5 g,0.051 mole) while stirring under argon. The resulting yellow slurry wasstirred at 5° C. for 30 min, then cooled to −65° C. Sodium methoxide(5.5 gm, 0.1 mole) in anhydrous methanol (50 mL) was added dropwise tothe cold mixture over a 30 min period. The mixture was allowed to warmto rt and was then quenched by dropwise addition of water (25 mL). Themixture was stirred for 5 min and the resulting crude light yellow solidwas filtered and washed with water. The solid was suspended in ether(200 mL), then filtered and washed with ether to yield Compound 4b (8.0g, 68%) as a light yellow solid. ¹H NMR (DMSO-d₆) δ 8.55 (d, 1H), 8.15(s, 1H), 7.55 (d, 1H), 7.3 (d, 1H), 3.9 (s, 3H).

A mixture of Compound 4b (2.37 g, 0.01 mole) and 1,2-dibromoethane (9.4g, 0.05 mole) in anhydrous DMF (25 mL) was stirred at rt under argon andtreated with cesium carbonate (6.5 g, 0.02 mole). The mixture was heatedto 30° C. for 4 h then stirred over night at rt. The white solids werefiltered and partitioned between ether (300 mL) and water (3×100 mL),then a brine solution (50 mL). The organic layer was dried overanhydrous sodium carbonate and concentrated in vacuo to give a crudeyellow oil. The crude oil was triturated with hexane to produce a crudesolid. The solid was then flash chromatographed on silica with 1:1 ethylacetate:hexane to give Compound 4c (1.9 g, 56%) as a light yellow solid.¹H NMR (DMSO-d₆) δ 8.65 (s, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.35 (d, 1H),4.8 (t, 2H), 3.95 (t, 2H), 3.9 (s, 3H).

A mixture of Compound 1e (prepared in Example 1) (0.86 g, 0.0049 mole),potassium carbonate (4.1 g, 0.029 mole) andN,N-dimethyl-3-chloropropylamine hydrochloride (3.87 g, 0.0245 mole) inanhydrous DMF (25 mL) was warmed to 70° C. and stirred under argon for 4h. After stirring over night at rt, the mixture was diluted with brine(50 mL) and extracted with ethyl acetate (3×150 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated in vacuo togive a tan solid Compound 4d (400 mg, 32%) as a 9:1 mixture of twoisomeric products. Evaluation of the ¹H NMR of the mixture concludedthat the N-1 substituted isomer was the major component. Majorcomponent: ¹H NMR (DMSO-d₆) δ 7.9-7.1 (m, 6H), 4.45 (t, 2H), 3.75 (s,2H), 3.1 (m, 2H), 2.75 (m, 6H), 2.18 (m, 2H); ES-MS m/z 261 (MH⁺). Minorcomponent: ¹H NMR (DMSO-d₆) δ 7.9-7.1 (m, 6H), 4.49 (t, 2H), 4.05 (s,2H), 3.3 (m, 2H), 3.1 (s, 6H), 2.0-2.3 (m, 2H); ES-MS m/z 261 (MH⁺).

Compound 4d (208 mg, 0.0008 mole) and Compound 4c (413 mg, 0.0012 mole)were combined in anhydrous THF (3 mL) and the mixture was stirred underargon while cooling in an ice bath. The mixture was then treateddropwise with a 1 N solution of potassium t-butoxide in THF (4.8 mL)over a 5 min period. The mixture was allowed to warm to rt and stirringcontinued another 5 h. The dark reaction mixture was then diluted withethyl acetate (100 mL) and washed with a 10% sodium carbonate solution(10 mL) followed by brine (2×10 mL). The organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give acrude product (380 mg) containing two major components. Minor impuritieswere removed by flash column chromatography on silica (eluting with a9:1 mixture of dichloromethane:methanol) to give of a 9:1 mixture ofCompound 6 and Compound 29, respectively (200 mg, 53%). Separation of a40 mg sample of the isomeric indazoles was accomplished by thick layer(2000μ) plate chromatography on silica eluted with an 85:13:2 mixture ofchloroform:methanol:ammonia to give Compound 6 (22 mg) and Compound 29(5 mg). For Compound 6: ¹H MNR (CDCl₃) δ 8.35 (s, 1H), 7.75 (d, 1H),7.65 (d, 1H), 7.6-7.05 (m, 5H), 6.25 (s, 1H), 5.45 (d, 1H), 5.05 (d,1H), 4.4 (t, 2H), 2.25 (t, 2H), 2.20 (s, 6H), 1.85 (t, 2H); ES-MS m/z474 (MH⁺). For Compound 29: ¹H NMR (CDCl₃) δ 8.15 (s, 1H), 7.7 (d, 1H),7.3-6.8 (m, 6H), 5.8 (s, 1H), 5.3 (d, 1H), 4.9 (d, 1H), 4.65-4.2 (m,2H), 2.6-2.2 (m, 8H), 1.9 (t, 2H); ES-MS m/z 474 (MH⁺).

Using the procedure of Example 4 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 33-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-(1-ethenyl- 4401H-indol-3-yl)-1H-pyrrole-2,5-dione 53-[5-chloro-1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4- 474(1-ethenyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione 283-[2-[2-(dimethylamino)ethyl]-2H-indazol-3-yl]-4-(1-ethenyl- 4401H-indol-3-yl)-1H-pyrrole-2,5-dione 1203-(5-chloro-2-ethyl-2H-indazol-3-yl)-4-[1-[3-(4- 518morpholinyl)propyl]-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1213-[2-(3-hydroxypropyl)-2H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H- 464indol-3-yl]-1H-pyrrole-2,5-dione 1223-[2-[2-(dimethylamino)ethyl]-2H-indazol-3-yl]-4-[1-(2- 526naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1233-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[2-[2- 532(dimethylamino)ethyl]-2H-indazol-3-yl]-1H-pyrrole-2,5-dione 1243-(5-chloro-1-methyl-1H-indol-3-yl)-4-[2-(3-hydroxypropyl)- 4352H-indazol-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 53-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(Compound 42)3-[2-[3-(dimethylamino)propyl]-2H-indazol-3-yl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(Compound 56)

Over a 10 min period, a 1.0 N solution of potassium t-butoxide in THF(2.2 mL, 2.2 mmol) was added dropwise to a suspension of Compound 3a(135 mg, 0.63 mmol) and Compound 4d (115 mg, 0.44 mmol) in anhydrous THF(1 mL) cooled to 0° C. The mixture was stirred at 0° C. for 10 min andrt for 3 h. The resulting dark reaction mixture was then diluted withethyl acetate 50 mL of and washed with water and brine, then dried overNa₂SO₄ and concentrated in vacuo. The residue was separated by prep.TLC(CH₂Cl₂:MeOH:NH₄OH; 85:13:2) to afford two isomers, Compound 42 (110mg, 58% yield) and Compound 56 (8 mg, 4% yield). Compound 42 wasdissolved in MeOH and 1.0 N HCl in Et₂O was added. The volatiles wereevaporated in vacuo to give the HCl salt of Compound 42 (120 mg) as ared-orange solid. For Compound 42: ¹H NMR (CD₃OD) δ 8.10 (s, 1H), 7.62(d, J=8.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.27 (d, J=8.3 Hz, 1H), 7.07 (t,J=7.3, 7.9 Hz, 1H), 6.92 (t, J=7.3, 7.8 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H),6.23 (d, J=8.1 Hz, 1H), 4.59 (t, J=5.8 Hz, 2H), 3.91 (s, 3H), 3.19 (t,J=6.9 Hz, 2H), 2.80 (s, 6H), 2.29 (m, 2H); ES-MS m/z 428 (MH⁺). Anal.calcd. for C₂₅H₂₅NO₂.1.25HCl 1.10H₂O: C, 60.92; H, 5.82; N, 14.21; Cl,8.99; KF, 4.02. Found: C, 61.13; H, 5.70; N, 14.16; Cl, 9.15; KF, 3.92.For Compound 56 (free base): ¹H NMR (CD₃OD) δ 8.29 (s, 1H), 7.63 (d,J=8.2 Hz, 1H), 7.44-7.30 (m, 3H), 7.08-7.00 (m, 2H), 6.54 (t, J=7.8 Hz,1H), 5.81 (d, J=7.5 Hz, 1H), 4.17 (m, 1H), 4.08 (m, 1H), 3.90 (s, 3H),2.20 (m, 3H), 2.13 (s, 6H), 1.89 (m, 1H); ES-MS m/z 428 (MH⁺).

EXAMPLE 63-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(3-pyridinylmethyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 26)

Compound 2b (203.2 mg, 0.001 mole) and cesium carbonate (1.3 g, 0.004mole) were combined in anhydrous DMF (5 mL). The mixture was stirredunder argon at 30° C. for 1 h, then 3-bromomethylpyridine hydrobromide(379 mg, 0.0015 mole) was added. The reaction mixture was stirred for anadditional 6 h and was then diluted with of ether (200 mL) and washedwith brine (2×50 mL). The organic layer was separated, then dried overanhydrous sodium sulfate and concentrated in vacuo to give Compound 6a(275 mg, 94%) as a brown oil. ¹H NMR (CDCl₃) δ 8.6 (m, 2H), 8.45 (m,2H), 7.5-7.25 (m, 5H), 5.4 (s, 2H), 3.95 (s, 3H). ES-MS m/z 295 (MH⁺).

Compound 6a (275 mg, 0.0009 mole) and Compound 1f (162 mg, 0.006 mole)were combined in anhydrous THF (10 mL). The mixture was stirred underargon and cooled in an ice bath while 1 N potassium t-butoxide in THF(3.6 mL) was added dropwise. The mixture was stirred an additional 5 minin an ice bath then at rt over night. The dark mixture was thenconcentrated in vacuo and flash chromatographed on silica (using a85:13:2 mixture of dichloromethane:methanol:ammonium hydroxide) to yieldCompound 26 (104 mg, 35%) as an orange solid. Compound 26 was dissolvedin water (5 mL) and adjusted to pH˜2 with 1 N hydrochloric acidsolution. The solution was freeze-dried overnight to give thehydrochloride salt. ¹H NMR (DMSO-d₆) δ 8.8 (m, 2H), 8.4 (s, 1H), 8.1 (d,1H), 7.85 (m, 1H), 7.75 (d, 1H), 7.6-7.35 (m, 3H), 7.2 (m, 2H), 6.75 (t,1H), 6.3 (d, 1H), 5.75 (s, 2H), 4.45 (t, 2H), 3.0 (m, 2H), 2.65 (s, 6H),2.05 (m, 2H). ES-MS m/z 505 (MH⁺).

Using the procedure of Example 6 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 73-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2- 454propenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 663-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(1- 554naphthalenylmethyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 673-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2- 555quinolinylmethyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 713-[1-[(2,6-dichlorophenyl)methyl]-1H-indol-3-yl]-4-[1-[3- 572(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 733-[1-[(5-chlorobenzo[b]thien-3-yl)methyl]-1H-indol-3-yl]-4-[1- 594[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 73-(5-chloro-1-ethyl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 46)

Compound 4b (119.2 mg, 0.0005 mole) and cesium carbonate (326 mg, 0.001mole) were combined in anhydrous DMF (5 mL) and the mixture was stirredat 30° C. under argon for 1 h. Iodoethane was then added dropwise andstirring continued at 30° C. to rt over night. The reaction mixture wasthen diluted with ether (100 mL) and partitioned with water (25 mL). Theorganic layer was separated and the aqueous layer extracted with ether(50 mL). The combined organic layers were washed with brine, then driedover anhydrous sodium sulfate and concentrated in vacuo to give Compound7a (110 mg, 81%) as a white solid.

Compound 1f (prepared in Example 1) (110 mg, 0.0004 mole) and Compound7a (70 mg, 0.00027 mole) were combined in anhydrous THF (3 mL) and themixture was stirred in an ice bath under argon. A 1 N solution ofpotassium t-butoxide in THF (1.6 mL, 0.0016 mole) was added dropwisewhile stirring under argon. The mixture was stirred an additional 3 h atrt and then evaporated in vacuo at rt to give the crude product. Thecrude product was purified via thick layer (2000,u) chromatography onsilica (eluted with dichloromethane:2% methanol) to give Compound 46 (18mg) as an orange glass. ES-MS m/z 476 (MH⁺). ¹H NMR (CDCl₃) δ8.15 (s,1H), 7.85 (d, 1H), 7.55 (d, 1H), 7.35 (t, 1H), 7.25 (d, 1H), 7.15 (t,1H), 7.05 (d, 1H), 6.15 (s, 1H), 4.4 (t, 2H), 4.15 (q, 2H), 2.25 (q,2H), 2.2 (s, 6H), 1.95 (m, 2H), 1.5 (t, 3H).

Using the procedure of Example 7 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 43 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-462 (dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 443-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-(1-ethyl- 4421H-indol-3-yl)-1H-pyrrole-2,5-dione 473-(5-chloro-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H- 448indazol-3-yl]-1H-pyrrole-2,5-dione 493-(4-chloro-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H- 448indazol-3-yl]-1H-pyrrole-2,5-dione 503-[5-chloro-1-(1-methylethyl)-1H-indol-3-yl]-4-[1-[3- 490(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione 523-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2- 458hydroxyethyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 553-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-(1H-indol- 4143-yl)-1H-pyrrole-2,5-dione 693-(1-ethyl-1H-indol-3-yl)-4-[1-[3-(4-morpholinyl)propyl]-1H- 518indazol-3-yl]-1H-pyrrole-2,5-dione 833-[1-[2-[2-(methylamino)ethoxy]ethyl]-1H-indazol-3-yl]-4-[1- 531[2-[2-(methylamino)ethoxy]ethyl]-1H-indol-3-yl]-1H-pyrrole- 2,5-dione

EXAMPLE 83-(5-chloro-1-phenyl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 48)

The indole Compound 4a (see Example 4) (3.02 g, 20 mmol) andbromobenzene (3.14 g, 20 mmol) were dissolved in DMF (10 mL). Potassiumcarbonate (2.76 g, 20 mmol) and CuO (130 mg, 1.6 mmol) were added andthe reaction was refluxed under argon for 16 h. The reaction was cooledto rt and partitioned between DCM (100 mL) and water (100 mL). Theorganic layer was washed with water (3×50 mL) and brine (2×50 mL), thendried (Na₂SO₄) and evaporated in vacuo to a brown oil. The oil waspurified via flash column chromatography (ethyl acetate:hexane; 1:10) togive Compound 8a (2.56 g, 56%) as a colorless oil.

Oxalyl chloride (0.52 g, 4.1 mmol) was added to the indole Compound 8a(0.91 g, 4.0 mmol) in diethyl ether (8 mL) while the mixture was cooledin an ice bath. The mixture was then stirred at ambient temperature for16 h, then cooled to −65° C. Sodium methoxide (0.46 g, 8.0 mmol) inmethanol (10 mL) was added slowly and the reaction was allowed to cometo rt. Water (5 mL) was added and the mixture was stirred for 30 min,then a light yellow solid Compound 8b (1.04 g, 83%) was filtered. ¹H NMR(CDCl₃) δ 8.60 (s, 1H), 8.55 (s, 1H), 7.65-7.25 (m, 7H), 3.98 (s, 3H).

The ester Compound 8b (56 mg, 0.18 mmol) and amide Compound 1f (40 mg,0.15 mmol, prepared in Example 1) were combined in dry THF (4 mL) underargon and cooled in an ice bath as 1 M potassium t-butoxide in THF (0.60mL, 0.60 mmol) was added with stirring over a 2 min period. Afterstirring for 2 h at rt, the reaction was quenched by slow addition of 12M HCl (0.25 mL, 3 mmol), stirred for 15 min and then partitioned betweenchloroform and saturated NaHCO₃. The organic solution was washed withsaturated NaHCO₃ and brine, then dried (Na₂SO₄) and evaporated in vacuoto a flaky solid. The solid was then purified by preparative thin layerchromatography (EtOAc:MeOH:NH₄OH; 80:16:2) to afford Compound 48 (26 mg,33%) as a flaky yellow solid. ¹H NMR (CDCl₃) δ 8.3 (s, 1H), 7.75 (d, J=7Hz, 1H), 7.60-7.30 (m, 8H), 7.20 (m, 1H), 7.08 (d, J=7 Hz, 1H), 6.28 (s,1H), 4.43 (m, 2H), 2.37 (m, 2H), 2.25 (s, 6H), 2.01 (m, 2H). ES-MS m/z524 (MH⁺).

Using the procedure of Example 8 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 45 3-[1-[3-(dimethylamino)propyl]-1H-indazol-3-490 yl]-4-(1-phenyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione 533-[1-[3-(dimethylamino)propyl]-1H-indazol-3- 504yl]-4-[1-(2-methylphenyl)-1H-indol-3-yl]-1H- pyrrole-2,5-dione 543-[1-(3-bromophenyl)-1H-indol-3-yl]-4-[1-[3- 568(dimethylamino)propyl]-1H-indazol-3-yl]-1H- pyrrole-2,5-dione

EXAMPLE 93-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2-propenyl)-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 30)3-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-(1H-indazol-3-yl)-1H-pyrrole-2,5-dione(Compound 57)3,4-bis[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 58)

Iodine (21.3 g, 84.0 mmol) was added to indazole Compound 9a (4.95 g,42.0 mmol) in DMF (80 mL) followed by KOH (8.84 g, 158 mmol). Thereaction mixture was stirred at rt for 1 h and was poured into 10%NaHCO₃ (260 mL), then extracted with Et₂O (2×200 mL). The combinedextracts were washed with water (100 mL) and brine (100 mL), then dried(Na₂SO₄) and evaporated in vacuo to give Compound 9b (10.0 g) as acolorless solid. EtMgBr (3.0 M in Et₂O, 6.0 mL, 18.0 mmol) was addeddropwise over a period of 10 min to a solution of indazole Compound 9b(1.22 g, 5.0 mmol) in THF (45 mL) cooled to 0° C. The reaction mixturewas then stirred at 0° C. for 20 min and a solution of Me₃SnCl (2.4 g,12.0 mmol) in THF (5 mL) was added dropwise over a 10 min. period. Themixture was stirred at 0° C. for 15 min then at rt for 10 min. SaturatedNH₄Cl (40 mL) was added followed by EtOAc (150 mL) and water (20 mL).The organic layer was separated, washed with water (40 mL) and brine (40mL), then dried (Na₂SO₄) and evaporated in vacuo to afford Compound 9c(1.35 g) as a light yellow solid.

Compound 9c (1.07 g, 3.8 mmol) was combined with1-benzyl-3,4-dibromomaleimde Compound 9d (438 mg, 1.27 mmol, prepared asdescribed in G. Xie, et al., Tetrahedron Lett., 1994, 35, 5555) and LiCl(215 mg, 5.08 mmol) in toluene (25 mL) under argon and Pd(PPh₃)₂Cl₂ (178mg, 0.25 mmol) was added. The reaction mixture was stirred at 90° C. for20 h and then diluted with EtOAc (150 mL), washed with water (60 mL) andbrine (60 mL), then dried (Na₂SO₄) and evaporated. The residue wasseparated by flash column chromatography (DCM:MeOH; 97:3) to affordCompound 9e (430 mg) as a red-orange solid. ¹H NMR (DMSO) δ 7.55 (d,J=8.1 Hz, 2H), 7.40-7.28 (m, 9H), 6.98 (t, J=7.3 Hz, 2H), 4.84 (s, 2H).ES-MS m/z 420 (MH⁺).

A mixture of Compound 9e (126 mg, 0.30 mmol) and K₂CO₃ (166 mg, 1.20mmol) in DMF (6 mL) was stirred at rt for 5 min and then3-dimethylaminopropylchloride hydrochloride (47 mg, 0.30 mmol) was addedportionwise. After stirring at 60° C. for 16 h, half of the reactionmixture was transferred to a separate round bottom flask and treatedwith allyl chloride (17 mg, 0.22 mmol). The resulting mixture wasstirred at 60° C. for 4 h, then diluted with EtOAc (60 mL), washed withwater (30 mL) and brine (20 mL), then dried (Na₂SO₄) and evaporated invacuo to give Compound 9f as a mixture of three products. The Compound9f mixture was dissolved in EtOH (5 mL) and KOH (84 mg, 1.5 mmol) wasadded. After stirring at 80° C. for 16 h, the reaction mixture wasdiluted with water (10 mL), acidified with 10% citric acid (10 mL) andextracted with EtOAc (40 mL). The aqueous solution was evaporated invacuo and the resulting residue was combined with neat NH₄OAc (10 g) andstirred at 140° C. for 1.5 h. The mixture was cooled to rt, dissolved inwater (30 mL), made basic with 3N NaOH to pH 10 and extracted with EtOAc(3×50 mL). The combined extracts were washed with water and brine, thendried (Na₂SO₄) and evaporated in vacuo. The residue was separated bypreparative TLC (DCM:EtOAc:MeOH:NH₄OH; 30:70:20:3) to afford Compound 30(2.2 mg). Compound 57 (1.0 mg) and Compound 58 (4.5 mg) were alsoisolated. For Compound 30: yellow-orange solid, ¹H NMR (CDCl₃) δ 7.46(d, J=8.5 Hz, 1H), 7.38-7.20 (m, 4H), 7.07 (d, J=8.3 Hz, 1H), 6.98-6.88(m, 2H), 5.93 (m, 1H), 5.21-5.08 (m, 2H), 5.04 (d, J=5.5 Hz, 2H), 4.42(t, J=6.9 Hz, 2H), 2.15 (s, 6H), 2.13 (m, 2H), 1.88 (t, J=6.8 Hz, 2H).ES-MS m/z 455 (MH⁺). For Compound 57: yellow-orange solid, ES-MS m/z 415(MH⁺). For Compound 58: yellow-orange solid, ¹H NMR (CDCl₃) δ 7.46 (d,J=8.6 Hz, 2H), 7.28 (m, 2H), 7.14 (d, J=8.2 Hz, 2H), 6.92 (t, J=8.2 Hz,2H), 4.45 (t, J=6.8 Hz, 4H), 2.26 (t, J=6.8 Hz, 4H), 2.21 (s, 12H), 1.97(t, J=6.8 Hz, 4H). ES-MS m/z 500 (MH⁺).

EXAMPLE 103-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1,5-dihydro-4-[1-(2-thienyl)-1H-indol-3-yl]-2H-pyrrol-2-one(Compound 36)4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1,5-dihydro-3-[1-(2-thienyl)-1H-indol-3-yl]-2H-pyrrol-2-one(Compound 37)

Compound 9 (0.85 g, 1.7 mmol) (prepared using the procedure of Example12) in THF (75 mL) was cooled in an ice bath as 1 M LAH in diethyl ether(10.5 mL, 10.5 mmol) was added over a 5 min period. The reaction mixturewas stirred at rt for 6 hr, then cooled in an ice bath as water (25 mL)was cautiously added with vigorous stirring. The solution was madeacidic (pH 2.0) with addition of 2N HCl and stirred at rt for 10 min.Saturated sodium bicarbonate was added until the pH was greater than9.0. The solution was then extracted with ethyl acetate. The organicextract was washed with brine (2×), then dried (K₂CO₃) and evaporated invacuo to a yellow solid (0.90 g). The material was purified by flashcolumn chromatography on 200 g of silica gel (eluting with ethylacetate:methanol:ammonium hydroxide; 80:20:2). The impure faster elutinglactam Compound 36 (200 mg) was collected first, then the slower isomerCompound 37 (80 mg). The first lactam was flash column chromatographed asecond time (50 g silica) to afford Compound 36 (60 mg): ¹H NMR (CDCl₃)δ 7.70 (s, 1H), 7.55 (d, J=8 Hz, 1H), 7.40 (d, J=8 Hz, 1H), 7.30-6.75(m, 9H), 4.67 (s, 2H), 4.45 (m, 2H), 2.25 (m, 2H), 2.20 (s, 6H), 2.05(m, 2H); ES_MS m/z 482 (MH⁺). The second lactam was purified bypreparative thin layer chromatography (DCM:methanol:ammonium hydroxide;80:16:1) to afford Compound 37 (25 mg): ¹H NMR (CDCl₃) δ 7.78 (s, 1H),7.75 (d, J=8 Hz, 1H), 7.50-6.90 (m, 10H), 4.73 (s, 2H), 4.43 (m, 2H),2.25 (m, 2H), 2.20 (s, 6H), 2.05 (m, 2H); ES-MS m/z 482 (MH⁺).

EXAMPLE 113-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 14)

Following the procedure of Example 1, using 2-bromonaphthalene in placeof 3-bromopyridine, a 1-(2-naphthalenyl)-indol-3-yl glyoxylic methylester analog of Compound 1c was filtered off as a light yellow solid(1.23 g, 94%). ¹H NMR (CDCl₃) δ 8.68 (s, 1H), 8.55 (d, J=7 Hz, 1H), 8.0(m, 4H), 7.6 (m, 4H), 7.38 (m, 2H), 3.98 (s, 3H).

The 1-(2-naphthalenyl)-indol-3-yl glyoxylic methyl ester (1.18 g, 3.6mmol) and amide Compound 1f (0.78 g, 3.0 mmol) were combined in dry THF(20 mL) under argon and cooled with an ice bath as 1 M potassiumt-butoxide in THF (12 mL, 12 mmol) was added with stirring over an 8 minperiod. After 1.1 h stirring, the reaction was quenched in an ice bath,12 N HCl (5.0 mL, 60 mmol) was slowly added over a 3 min period. Themixture was stirred for 15 min and then partitioned between chloroform(125 mL) and saturated NaHCO₃. The organic solution was washed withsaturated NaHCO₃ and brine, then dried (Na₂SO₄) and evaporated in vacuoto a flaky solid. The solid was then purified by flash columnchromatography (80:16:2 ethyl acetate:MeOH:NH₄OH) to afford Compound 14(1.32 g, 82%) as an orange flaky solid. Compound 14 was crystallizedfrom ethyl acetate:methanol (10:1, 10 mL) as an orange solid (1.02 g).The solid was then dissolved in DCM (20 mL) containing methanol (5 mL).1 N HCl in diethyl ether (3.0 mL, 3.0 mmol) was added. The solution wasevaporated in vacuo to give Compound 14 (1.31 g) as a red solid.Compound 14 was dissolved in water (100 mL) with slight warming, thenfrozen and lyophilized to give the hydrochloride salt. ¹H NMR (DMSO) δ8.44 (s, 1H), 8.22 (s, 1H), 8.19 (m, 1H), 8.09 (m, 2H), 7.84-7.60 (m,6H), 7.47 (dd, 1H, J=7.5, 7.6 Hz), 7.18 (dd, 2H, J=7.5, 7.7 Hz), 6.86(dd, 1H, J=7.5, 7.6 Hz), 6.47 (d, 1H, J=8.0 Hz), 4.49 (t, 2H, J=6.8 Hz),2.93 (m, 2H), 2.57 (s, 6H), 2.03 (m, 2H). ES-MS m/z 540 (MH⁺). Anal.Calcd. for C₃₄H₂₉N₅O₂.2.0H₂O.1.5HCl: C, 64.78; H, 5.51; N, 11.11; KF,5.71. Found: C, 65.15; H, 5.51; N, 11.29; KF, 6.19.

EXAMPLE 123-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(2-thienyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 9)

Following the procedure of Example 1, using 2-bromothiophene in place of3-bromopyridine, a 1-(2-thienyl)-indol-3-yl glyoxylic methyl esteranalog of Compound 1c was prepared. ¹H NMR (CDCl₃) δ 8.55 (s, 1H), 8.47(m, 1H), 7.55 (m, 1H), 7.40 (m, 2H), 7.33 (dd, J=1.4, 5.5 Hz, 1H), 7.22(dd, J=1.4, 3.7 Hz, 1H), 7.12 (dd, J=3.7, 5.5 Hz, 1H), 3.97 (s, 3H).

The 1-(2-thienyl)-indol-3-yl glyoxylic methyl ester (787 mg, 2.76 mmol)and amide Compound 1f (600 mg, 2.3 mmol) were combined in dry THF (10mL) under argon and cooled in an ice bath as 1 M potassium t-butoxide inTHF (9.2 mL, 9.2 mmol) was added with stirring over a 20 min period.After 1 h, the reaction was quenched in an ice bath, 12 N HCl (3.5 mL,42 mmol) was slowly added over a 3 min period. The mixture was stirredfor an additional 5 min and then partitioned betweenchloroform:2-propanol (10:1, 200 mL) and saturated NaHCO₃. The organicsolution was washed with brine, then dried (Na₂SO₄) and evaporated invacuo to a flaky solid (1.1 g, 98%). The solid was purified by flashcolumn chromatography (90:9:1; DCM:MeOH:NH₄OH) to afford Compound 9(0.84 g, 69%) as an orange flaky solid. A portion of Compound 9 wasdissolved in excess dilute HCl, then frozen and lyophilized to give thehydrochloride salt. ¹H NMR (DMSO) δ 8.26 (s, 1H), 8.76 (m, 2H), 7.62 (m,2H), 7.44 (m, 2H), 7.20 (m, 3H), 6.86 (dd, J=7.5, 7.7 Hz, 1H), 6.47 (d,J=8.0 Hz, 1H), 4.45 (dd, J=6.9, 7.0 Hz, 2H), 2.90 (m, 2H), 2.50 (s, 6H),1.99 (m, 2H). ES-MS m/z 496 (MH⁺). Anal. Calcd. forC₂₈H₂₅N₅O₂S.HCl.1.5H₂O (495.6/559.08): C, 60.15; H, 5.22; N, 12.53; H₂O,4.83. Found: C, 59.87; H, 4.96; N, 12.45; H₂O, 4.39.

EXAMPLE 133-(4-chloro-1-ethenyl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 10)

Following the procedure of Example 4, using 4-chloroindole Compound 13ain place of the 5-chloroindole Compound 4a, a mixture of Compound 13a(2.0 g, 0.013 mole) in ether (50 mL) was cooled in an ice bath andtreated dropwise with 1.66 g (0.013 mole) of oxalyl chloride whilestirring under argon. The resulting yellow slurry was stirred at 5° C.for 30 min then cooled to −65° C. A solution of sodium methoxide (1.42g, 0.026 mole) in anhydrous methanol (25 mL) was added dropwise to thecold mixture over a 30 min period then the mixture was allowed to warmto rt. The mixture was then quenched by dropwise addition of water (20mL), stirred for 5 min and the resulting two phase mixture wasseparated. The water layer was washed with 30 mL of ether. The combinedether extracts were washed with brine and dried over anhydrous potassiumcarbonate. The solvent was removed in vacuo to give Compound 13b (2.6 g)that gradually crystallized. The crude product was used in the next stepwithout further purification. A mixture of Compound 13b (1.0 g, 0.0042mole) and 1,2-dibromoethane (3.9 g, 0.021 mole) in anhydrous DMF (20 mL)was stirred at rt under argon and treated with cesium carbonate (2.74 g,0.0084 mole). The mixture was heated to 50° C. for 4 h then stirred overnight at rt. The white solids were filtered and washed with ethylacetate (150 mL). The filtrate was partitioned with three portions ofwater then one portion of brine. The organic layer was separated, thendried over anhydrous sodium sulfate and concentrated in vacuo to give a60/40 mixture of Compound 13c and Compound 13d (162 mg) as a lightyellow oil. The oil was used in the next step without furtherpurification.

The ester Compound 13c and Compound 13d (150 mg, as a mixture) and amideCompound 1f (84 mg, 0.0003 mole) were combined in dry THF (5 mL) underargon and cooled in an ice bath as 1 M potassium t-butoxide in THF (1.8mL) was added dropwise with stirring over a 5 min period. The mixturewas stirred at rt for 2 h then spotted on a 20001 silica prep plate andeluted with a 85:13:2 mixture of ethyl acetate:methanol:ammonia. Thespot containing the product was scraped and washed free of the silicawith a 90:10 mixture of chloroform:methanol. The solvent was removed invacuo to give Compound 10 as a bright orange solid. ES-MS m/z 474 (MH⁺).

EXAMPLE 143-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-(1-ethyl-5-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione(Compound 51)

Following the procedure of Example 4, using 5-methylindole in place of5-chloroindole, 5-methylindole (2.0 g, 0.0152 mole) in a mixture withether (50 mL) was cooled in an ice bath and treated dropwise with oxalylchloride (1.96 g, 0.0154 mole) while stirring under argon. The resultingyellow slurry was stirred at 5° C. for 30 min then cooled to −65° C. Asolution of sodium methoxide (1.7 g, 0.031 mole) in anhydrous methanol(25 mL) was added dropwise to the cold mixture over a 30 min period,then the mixture was allowed to warm to rt. The mixture was then cooledin an ice bath, quenched by dropwise addition of water (50 mL) andstirred for 5 min. The resulting three phase mixture was filtered andthe solids were washed with water then air dried to give a5-methylindole methyl ester analog of Compound 4b (2.8 g). The crudeproduct was used in the next step without further purification.

Following the procedure of Example 7, a mixture of the 5-methylindolemethyl ester (217 mg, 0.001 mole) and cesium carbonate (650 mg, 0.002mole) in anhydrous DMF (10 mL) was stirred at 30° C. under argon for 1h. Iodoethane (780 mg, 0.005 mole) was then added dropwise and stirringcontinued at 25-30° C. overnight. The reaction mixture was then dilutedwith ether (150 mL) and partitioned with water (25 mL). The organiclayer was separated and the aqueous layer extracted with ether (50 mL).The combined organic layers were washed with brine, then dried overanhydrous sodium sulfate and concentrated in vacuo to give a N-ethylsubstituted 5-methylindole methyl ester analog of Compound 7a (233 mg)as a clear oil. The oil was used in the next step without furtherpurification.

A mixture of Compound 1f (see Example 1) (35 mg, 0.13 mmol) and theN-ethyl substituted 5-methylindole methyl ester (50 mg, 0.2 mmol) inanhydrous THF (5 mL) was stirred in an ice bath under argon. Then a 1 Nsolution of potassium t-butoxide in THF (0.8 mL, 0.0008 mole) was addeddropwise while stirring under argon. The mixture was stirred for anadditional 3 h at rt and then evaporated in vacuo at rt to give thecrude product. The crude product was purified via preparative TLC,eluted with an 85:13:2 mixture of dichloromethane:methanol:ammonia togive of Compound 51 (1.5 mg) as an orange glass. ES-MS m/z 456 (MH⁺).

Using the procedure of Example 14 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 81 3-[1-[3-(dimethylamino)propyl]-1H-indazol-472 3-yl]-4-(1-ethyl-5-methoxy-1H-indol-3-yl)-1H- pyrrole-2,5-dione 863-(5-chloro-1-ethyl-1H-indazol-3-yl)-4-[1-[3- 518(4-morpholinyl)propyl]-1H-indol-3-yl]-1H- pyrrole-2,5-dione 873-(5-chloro-1-ethyl-1H-indazol-3-yl)-4-[1-[3- 531(4-methyl-1-piperazinyl)propyl]-1H-indol-3- yl]-1H-pyrrole-2,5-dione 963-(5-chloro-1-ethyl-1H-indazol-3-yl)-4-[1-[3- 502(1-pyrrolidinyl)propyl]-1H-indol-3-yl]-1H- pyrrole-2,5-dione

EXAMPLE 153-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(1-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 15)

Following the procedure of Example 1, using 1-bromonaphthalene in placeof 3-bromopyridine, a 1-(1-naphthyl)-indol-3-yl glyoxylic methyl esteranalog of Compound 1c was prepared. ¹H NMR (CDCl₃) δ 8.60 (s, 1H), 8.56(d, J=8.0 Hz, 1H), 8.05 (m, 3H), 7.65 (m, 4H), 7.40-7.20 (m, 2H), 7.01(m, 1H), 3.97 (s, 3H).

The 1-(1-naphthyl)-indol-3-yl glyoxylic methyl ester (59 mg, 0.18 mmol)and amide Compound 1f (40 mg, 0.15 mmol) were combined in THF (2.0 mL)with 1 M potassium t-butoxide in THF (0.60 mL, 0.60 mmol) at 0° C. toafford an orange solid (90 mg). The solid was purified using preparativesilica TLC plates (1500,u; EtOAc:MeOH:NH₄OH; 40:8:1) to give Compound 15(37 mg, 46%) as an orange solid. ES-MS m/z 540 (MH⁺). ¹H NMR (CDCl₃) δ8.30 (s, 1H), 7.99 (m, 2H), 7.74 (d, J=8.2 Hz, 1H), 7.55 (m, 4H), 7.41(m, 3H), 7.14 (dd, J=7.4, 7.5 Hz, 1H), 6.95 (m, 2H), 6.79 (dd, J=7.0,8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.41 (dd, J=6.9, 7.0 Hz, 2H), 2.15(m, 2H), 2.12 (s, 6H), 1.88 (m, 2H).

EXAMPLE 163-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(4-isoquinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 16)

Following the procedure of Example 1, using 4-bromoisoquinoline in placeof 3-bromopyridine, a 1-(4-isoquinolinyl)-indol-3-yl glyoxylic methylester analog of Compound 1c was prepared. ¹H NMR (CDCl₃) δ9.45 (s, 1H),8.70 (s, 1H), 8.63 (s, 1H), 8.58 (d, J=7.9 Hz, 1H), 8.19 (m, 1H), 7.75(m, 2H), 7.50 (m, 2H), 7.29 (m, 1H), 7.02 (d, J=8.3 Hz, 1H), 3.96 (s,3H).

The 1-(4-isoquinolinyl)-indol-3-yl glyoxylic methyl ester (175 mg, 0.53mmol) and amide Compound 1f (117 mg, 0.45 mmol) were combined in THF(5.0 mL) with 1M potassium t-butoxide in THF (1.80 mL, 1.80 mmol) at 0°C. to afford an orange solid (250 mg). The solid was purified usingflash column chromatography (EtOAc:MeOH:NH₄OH; 40:4:1) to give Compound16 (100 mg, 41%) as an orange solid. Compound 16 was dissolved inaqueous HCl, then frozen and lyophilized to the hydrochloride salt (115mg, 40%). ES-MS m/z 541 (MH⁺). ¹H NMR (DMSO) δ 9.60 (s, 1H), 8.95 (s,1H), 8.40 (d, J=8.0 Hz, 1H), 8.28 (s, 1H), 7.85 (m, 3H), 7.65 (d, J=8.2Hz, 1H), 7.48 (m, 1H), 7.18 (m, 3H), 7.0 (m, 1H), 6.91 (m, 1H), 6.68 (d,J=8.0 Hz, 1H), 4.52 (m, 2H), 3.0 (m, 2H), 2.61 (s, 6H), 2.10 (m, 2H).

EXAMPLE 173-[5-chloro-2-methyl-1-(3-pyridinyl)-1H-indol-3-yl]-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 20)

Following the procedure of Example 1, using 2-Me-5-Cl-indole (2.00 g,17.1 mmol) in place of indole Compound 1a, a1-(3-pyridinyl)-5-chloro-2-methyl-indol-3-yl glyoxylic methyl esteranalog of Compound 1c (2.6 g) was obtained as an amber gum. The productwas used in the next step without further purification.

The 1-(3-pyridinyl)-5-chloro-2-methyl-indol-3-yl glyoxylic methyl ester(492 mg, 0.0015 mole) and amide Compound 1f (260 mg, 0.001 mole) werecombined in dry THF (10 mL) under argon and cooled in an ice bath as 1 Mpotassium t-butoxide in THF (6 mL) was added with stirring over a 20 minperiod. After 4 h, the reaction stripped in vacuo to give a darkresidue. The residue was purified by flash column chromatography onsilica using an 85:13:2 mixture of methylene chloride:methanol:ammoniato elute the product. The eluant was stripped in vacuo to affordCompound 20 (0.26 g) as an orange flaky solid. Compound 20 was dissolvedin one equivalent of dilute HCl, then frozen and lyophilized to give thehydrochloride salt. ¹H NMR (DMSO-d₆) δ 8.80 (d, 1H), 8.60 (s, 1H), 7.95(d, 1H), 7.80-7.70 (m, 2H), 7.35 (t, 1H), 7.30-7.20 (m, 2H), 7.10-7.00(m, 3H), 4.60-4.50 (t, 2H), 3.15-3.00 (m, 2H), 2.65 (2s, 6H), 2.20-2.00(m, 2H), 1.80 (s, 3H). ES-MS m/z 539 (MH⁺).

EXAMPLE 183-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-4-[1-(5-pyrimidinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 34)

Following the procedure of Example 1, using 5-bromopyrimidine (2.72 g,17.1 mmol) in place of 3-bromopyridine, a 1-(5-pyrimidinyl)-indol-3-ylglyoxylic methyl ester analog of Compound 1c was obtained as a yellowsolid (260 mg, 25%). ¹H NMR (CDCl₃) δ 9.36 (s, 1H), 9.04 (s, 2H), 8.62(s, 1H), 8.56-8.53 (m, 1H), 7.49-7.42 (m, 3H), 3.91 (s, 3H). ES-MS m/z282 (MH⁺).

The 1-(5-pyrimidinyl)-indol-3-yl glyoxylic methyl ester (219 mg, 0.78mmol) and amide Compound 1f (150 mg, 0.58 mmol) were combined in dry THF(15 mL) under nitrogen and cooled in an ice bath as 1 M potassiumt-butoxide in THF (2.3 mL, 2.3 mmol) was added with stirring over a 5min period. After 2 h, the reaction was quenched in an ice bath, 12N HCl(0.97) was slowly added and the mixture was stirred for 15 min. Thereaction was diluted with chloroform (43 mL) and washed with saturatedNaHCO₃ (2×15 mL) and brine (15 mL), then dried (K₂CO₃) and evaporated invacuo to a solid. The solid was purified by flash column chromatography(91:7:2; DCM:MeOH:NH₄OH) to afford Compound 34 (0.069 g, 24%) as a redsolid. The product was dissolved in 1 N HCl:CH₃CN (2:1), then frozen andlyophilized to give the hydrochloride salt. ¹H NMR (DMSO-d₆) δ 9.31 (s,1H), 9.21 (s, 2H), 8.45 (s, 1H), 7.81 (dd, J=8.53, 8.25 Hz, 2H), 7.59(d, J=8.36 Hz, 1H), 7.49-7.41 (m, 1H), 7.24-7.16 (m, 2H), 6.88 (t,J=7.76 Hz, 1H), 6.49 (d, J=7.95 Hz, 1H), 4.46 (t, J=6.83, 6.99 Hz, 2H),3.09-2.93 (m, 2H) 2.60 (s, 6H), 2.29-1.91 (m, 2H). ES-MS m/z 492 (MH⁺).Anal. Calcd. For C₂₈H₂₅N₇O₂.1.73HCl.1.89H₂O (491.54/588.67): C, 57.13;H, 5.23; N, 16.66; Cl, 10.42; KF, 5.79. Found: C, 56.76; H, 5.50; N,17.43; Cl, 9.99; KF, 5.43.

EXAMPLE 193-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-[1-(3-pyridinyl)-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 59)

The indol-3-yl-glyoxylic methyl ester (0.50 g, 2.46 mmol) Compound 2band 3-dimethylamino propyl chloride hydrochloride (0.44 g, 2.78 mmol)were combined in DMF (5 mL) and cooled to 0° C. as 95% NaH (135 mg, 5.34mmol) was added. The reaction vessel was placed in an oilbath at 55° C.for 20 h and then cooled to ambient temperature. The solution wasdiluted with DCM (30 mL), washed with water, 3 times with saturatedNaHCO₃ and once with brine, then dried (K₂CO₃) and evaporated in vacuoto give an oil (0.44 g, 62%). The oil was purified via flash column(DCM:MeOH; 10:1) to afford Compound 19a. ES-MS m/z 289 (MH⁺).

Following the procedure for converting Compound 1a to Compound 1b, theindazole Compound 1e (350 mg, 2.0 mmol) was combined with3-bromopyridine (332 mg, 2.1 mmol) to give a crude product Compound 19b(410 mg). Compound 19b was purified by flash column chromatography(DCM:MeOH; 10:1) to a tan solid. ES-MS m/z 253 (MH⁺). ¹H NMR (CDCl₃) δ9.1 (s, 1H), 8.62 (d, J=2 Hz, 1H), 8.1 (d, J=8.0 Hz, 1H), 7.75 (m, 2H),7.50 (m, 2H), 7.34 (m, 1H), 4.10 (s, 2H).

Following the procedure of Example 1, the ester Compound 19a (55 mg,0.19 mmol) and the amide Compound 19b (37 mg, 0.147 mmol) in THF (3 mL)were combined with 1 M potassium t-butoxide in THF (0.60 mL, 0.60 mmol)at 0° C. to give a crude product Compound 59 (60 mg) as an orange solid.Compound 59 was then purified by flash column chromatography(DCM:MeOH:NH₄OH; 90:9:1) (50 mg, 69%), then dissolved in aqueous HCl,then frozen and lyophilized to the hydrochloride salt. ES-MS m/z 491(MH⁺). ¹H NMR (DMSO) δ 8.54 (m, 2H), 8.31 (s, 1H), 7.90 (m, 3H), 7.6 (m,3H), 7.32 (dd, J=7.4, 7.7 Hz, 1H), 7.11 (dd, J=7.3, 7.7 Hz, 1H), 6.69(dd, J=7.4, 7.7 Hz, 1H), 6.23 (d, J=8.0 Hz, 1H), 4.42 (m, 2H), 3.08 (m,2H), 2.73/2.75 (2 s, 6H), 2.21 (m, 2H).

EXAMPLE 203-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 60)

Following the procedure of Example 1, using 3-bromobenzo[b]thiophene(3.64 g, 17.1 mmol) in place of 3-bromopyridine, a1-(3-benzo[b]thienyl)-indol-3-yl glyoxylic methyl ester analog ofCompound 1c was obtained as a yellow solid (0.97 g, 69%). ¹H NMR (CDCl₃)δ 8.55 (s, 1H), 8.47 (d, J=7.9 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H), 7.60 (s,1H), 7.44-7.18 (m, 6H), 3.89 (s, 3H). ES-MS m/z 336 (MH⁺).

The 1-(3-benzo[b]thienyl)-indol-3-yl glyoxylic methyl ester (272 mg,0.81 mmol) and amide Compound 1f (150 mg, 0.58 mmol) were combined indry THF (8 mL) under nitrogen and cooled in an ice bath as 1 M potassiumt-butoxide in THF (2.3 mL, 2.3 mmol) was added with stirring over a 15min period. The reaction was warmed to rt and stirred at rt for 3 h. Thereaction was diluted with ethyl acetate (138 mL) and washed with water(2×28 mL), saturated NaHCO₃ (56 mL) and brine (56 mL), then dried(Na₂SO₄) and evaporated in vacuo to provide a solid. The solid waspurified by flash column chromatography (97.5:0.5:2; DCM:MeOH:NH₄OH) toafford Compound 60 (0.12 g, 40%) as a red solid. Compound 60 wasdissolved in 1 N HCl:CH₃CN (2:1), then frozen and lyophilized to givethe hydrochloride salt. ¹H NMR (free base, CDCl₃) δ 8.29 (s, 1H), 7.94(d, J=8.0 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.60 (s, 1H), 7.55-7.35 (m,5H), 7.23-7.04 (m, 3H), 6.80 (t, J=7.2 Hz, 1H), 6.57 (d, J=8.0 Hz, 1H),4.40 (t, J=6.94 Hz, 2H), 2.26-2.13 (m, 8H), 1.89-1.62 (m, 2H). ES-MS m/z546 (MH⁺). Anal. Calcd. For C₃₂H₂₇N₅O₂S.1.03HCl*1.75H₂O (545.66/614.74):C, 62.53; H, 5.17; N, 11.40; Cl, 5.95; KF, 5.13. Found: C, 62.32; H,4.98; N, 11.53; Cl, 5.93; KF, 5.11.

EXAMPLE 213-(1-[1,1′-biphenyl]-3-yl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 61)

Following the procedure of Example 1, using 3-bromobiphenyl (2.13 mL,12.8 mmol) in place of 3-bromopyridine, a 1-(3-phenyl-phenyl)-indol-3-ylglyoxylic methyl ester analog of Compound 1c was obtained as a yellowsolid (1.01 g, 77%). ¹H NMR (CDCl₃) δ 8.63 (s, 1H), 8.53 (d, J=7.22 Hz,1H), 7.75-7.62 (m, 4H), 7.55-7.33 (m, 8H), 3.97 (s, 3H). ES-MS m/z 356(MH⁺).

The 1-(3-phenyl-phenyl)-indol-3-yl glyoxylic methyl ester (288 mg, 0.81mmol) and amide Compound 1f (150 mg, 0.58 mmol) were combined in dry THF(8 mL) under nitrogen and cooled in an ice bath as 1 M potassiumt-butoxide in THF (2.3 mL, 2.3 mmol) was added with stirring over a 15min period. The reaction was warmed to rt and stirred at rt for 2 h. Thereaction was diluted with ethyl acetate (138 mL), washed with water(2×28 mL), saturated NaHCO₃ (56 mL) and brine (56 mL), then dried(Na₂SO₄) and evaporated in vacuo to give a solid. The solid was purifiedby flash column chromatography (97.5:0.5:2; DCM:MeOH:NH₄OH) to affordCompound 61 (0.099 g, 30%) as a red solid. Compound 61 was thendissolved in 1 N HCl:CH₃CN (2:1), then frozen and lyophilized to givethe hydrochloride salt. ¹H NMR (free base, CDCl₃) δ 8.34 (s 1H),7.80-7.38 (m, 13H), 7.26-7.08 (m, 2H), 6.77 (t, J=7.28, 7.25 Hz, 1H),6.46 (d, J=8.05 Hz, 1H), 4.37 (t, J=6.92, 6.96 Hz, 2H), 2.22-2.10 (m,8H), 1.85-1.78 (m, 2H). ES-MS m/z 566 (MH⁺). Anal. Calcd. forC₃₆H₃₁N₅O₂.1.14HCl.1.98H₂O (565.66/642.92): C, 67.26; H, 5.66; N, 10.90;Cl, 6.29; KF, 5.52. Found: C, 66.86; H, 5.62; N, 10.87; Cl, 5.50; KF,5.19.

Using the procedure of Example 21 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 723-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]- 5724-[1-[3-(3-thienyl)phenyl]-1H-indol-3-yl]-1H- pyrrole-2,5-dione

EXAMPLE 223-[1-[3-(4-morpholinyl)propyl]-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 68)

Following the procedure for converting Compound 1e to Compound 1f, theindazole Compound 1e (1.58 g, 9 mmol) in DMF (20 mL) was combined with3-chloropropylmorpholine (1.62 g, 9.90 mmol) and cooled in an ice bathas 95% NaH (sodium hydride) (0.25 g, 9.90 mmol) was added portionwiseover a 20 min period. The reaction was stirred at ambient temperaturefor 10 min and then placed in an oil bath at 55° C. for 2 h. Aftercooling to rt, the reaction was diluted with DCM (200 mL), washed 3times with brine (60 mL), then dried (K₂CO₃) and evaporated in vacuo togive an oil (2.60 g). The oil was purified by flash columnchromatography (EtOAc:MeOH:NH₄OH; 80:10:1) to afford a1-[3-(morpholino)propyl]-1H-indazol-3-yl analog of Compound 1f as awhite solid (1.34 g, 49%).

Following the procedure of Example 1, the1-[3-(morpholino)propyl]-1H-indazol-3-yl (151 mg, 0.50 mmol) and esterCompound 1c (170 mg, 0.6 mmol) were stirred in THF (5 mL) at 0° C. as 1M potassium t-butoxide in THF (2.0 mL, 2.0 mmol) was added over 3 minand reaction stirred for 1 h. The reaction was quenched at 0° C. withHCl (12N, 0.90 mL), stirred for 15 min and then poured into saturatedNaHCO₃ and extracted with chloroform. The organic solution was washedwith brine, then dried (Na₂SO₄) and evaporated in vacuo to give anorange solid. The solid was purified via flash column chromatography(EtOAc:MeOH:NH₄OH; 80:8:2) to give Compound 68 (160 mg, 62%) as anorange solid. Compound 68 was dissolved in aqueous HCl, then frozen andlyophilized to the hydrochloride salt (170 mg). ES-MS m/z 533 (MH⁺). ¹HNMR (CD₃OD, 300 MHz) δ 9.26 (s, 1H), 8.90 (m, 2H), 8.39 (s, 1H), 8.19(m, 1H), 7.66 (m, 2H), 7.55 (d, J=8.2 Hz, 1H), 7.43 (m, 1H), 7.21 (m,1H), 7.07 (m, 1H), 6.81 (dd, J=7.6, 7.7 Hz, 1H), 6.47 (d, J=8.0 Hz, 1H),4.54 (dd, J=6.4, 6.4 Hz, 2H), 3.98 (m, 2H), 3.75 (m, 2H), 3.38 (m, 2H),3.15 (m, 2H), 2.94 (m, 2H), 2.25 (m, 2H).

EXAMPLE 233-[1-[3-(4-morpholinyl)propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 70)

Following the procedure of Example 1 for combining Compound 1c andCompound 1f to obtain a target compound, the1-(2-naphthyl)-indol-3-yl-glyoxylic methyl ester (296 mg, 0.90 mmol)analog of Compound 1c (prepared in Example 11) in THF (6.0 mL) and the1-[3-(morpholino)propyl]-1H-indazol-3-yl (226 mg, 0.75 mmol) analog ofCompound 1f (prepared in Example 22) were combined with 1 M potassiumt-butoxide in THF (3.0 mL, 3.0 mmol) to afford a crude product. Theproduct was flash column purified to give Compound 70 (200 mg, 46%) asan orange solid. Compound 70 was dissolved in aqueous HCl, then frozenand lyophilized to afford the hydrochloride salt (219 mg). ES-MS m/z 582(MH⁺). ¹H NMR (CD₃OD, 300 MHz) δ 8.34 (s, 1H), 8.11 (d, J=8.8 Hz, 1H),8.05 (s, 1H), 7.98 (m, 2H), 7.60 (m, 6H), 7.45 (m, 1H), 7.13 (m, 2H),6.75 (dd, J=7.3, 7.8 Hz, 1H), 6.44 (d, J=8.1 Hz, 1H), 4.53 (dd, J=6.3,6.4 Hz, 2H), 3.80 (m, 4H), 3.01 (m, 6H), 2.22 (m, 2H).

EXAMPLE 243-[1-(3-hydroxypropyl)-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 84)

The indazole Compound 1e (5 g, 28.6 mmol) was combined with asilyl-protected 3-bromo-1-propanol Compound 24a (8.33 g, 32.9 mmol) inthe presence of Cs₂CO₃ (12.11 g, 37 mmol) in DMF (50 mL) at 68° C. for 3h. The mixture was cooled to rt, water was added and extracted withEtOAc several times. The organic layers were combined and washed withbrine, then dried (Na₂SO₄) and evaporated in vacuo to provide an oil.The oil was purified by flash column chromatography (95:5:0.5;DCM:MeOH:NH₄OH) to give an amide Compound 24b (9.9 g, 100%). ¹H NMR(CDCl₃) δ 7.65 (m, 1H), 7.38 (m, 2H), 7.13 (m, 1H), 6.53 (bd s, 1H),5.44 (bd s, 1H), 4.44 (t, J=6.82 Hz, 2H), 3.93 (s, 2H), 3.56 (t, J=5.73Hz, 2H), 2.08 (m, 2H), 0.89 (s, 9H), 0.01 (s, 6H). ES-MS m/z 348 (MH⁺).

The 1-(2-naphthyl)-indol-3-yl-glyoxylic methyl ester (0.13 g, 0.40 mmol)analog of Compound 1c (prepared in Example 11) and amide Compound 24b(0.1 g, 0.29 mmol) were combined in dry THF (8 mL) under argon andcooled in an ice bath as 1 M potassium t-butoxide in THF (1.4 mL, 1.4mmol) was added with stirring over a 5 min period. After 40 min, thereaction was quenched in an ice bath while 12 N HCl (2 mL, 24 mmol) wasslowly added over a 2 min period. The mixture was stirred for 5 min,made basic to slightly basic by the addition of 3N NaOH and extractedwith EtOAc. The organic layers were combined and washed with saturatedNaHCO₃ and brine, then dried (Na₂SO₄) and evaporated in vacuo to affordCompound 84 (72 mg, 49%) as an orange flaky solid. The solid was thenpurified by flash column chromatography (96:4:0.4; DCM:MeOH:NH₄OH). ¹HNMR (CDCl₃) δ 8.34 (s, 1H), 7.93 (m, 4H), 7.79 (m, 2H), 7.68 (d, J=2.13Hz, 1H), 7.58 (m, 3H), 7.44 (m, 1H), 7.16 (m, 2H), 6.78 (m, 1H), 6.50(d, J=8.0 Hz, 1H), 4.47 (t, J=6.3 Hz, 2H), 3.40 (t, J=5.8 Hz, 2H), 1.89(m, 2H). ES-MS m/z 513 (MH⁺).

Using the procedure of Example 24 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 91 3-[1-(4-hydroxybutyl)-1H-indazol-3-yl]-4-[1-527 (2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5- dione 923-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[1- 533(4-hydroxybutyl)-1H-indazol-3-yl]-1H-pyrrole-2,5- dione 993-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[1- 505(2-hydroxyethyl)-1H-indazol-3-yl]-1H-pyrrole-2,5- dione 1003-[1-(2-hydroxyethyl)-1H-indazol-3-yl]-4-[1- 499(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5- dione

EXAMPLE 253-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-hydroxypropyl)-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 74)

Following the procedure of Example 7, a N-methyl substituted indolemethyl ester analog of Compound 7a (0.37 g, 1.47 mmol) and the amideCompound 24b (0.34 g, 0.98 mmol) (prepared in Example 24 and containinga small amount of the N-2 alkylated indazole isomer) were combined indry THF (5 mL) under argon and cooled in an ice bath as 1 M potassiumt-butoxide in THF (4.9 mL, 4.90 mmol) was added with stirring over a 10min period. After 40 min, the reaction was quenched in an ice bath while12 N HCl (5 mL, 60 mmol) was slowly added over a 5 min period. Themixture was stirred for 10 min, then made basic to slightly basic with3N NaOH and extracted with EtOAc. The organic layers were combined andwashed with saturated NaHCO₃ and brine, then dried (Na₂SO₄) andevaporated in vacuo to afford Compound 74 (0.13 g, 30%) as an orangeflaky solid. Compound 74 was then purified by flash columnchromatography (96:4:0.4; DCM:MeOH:NH₄OH). ¹H NMR (CD₃OD) δ 8.14 (s,1H), 7.63 (d, J=8.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.36 (m, 2H), 7.02(t, J=7.1 Hz, 2H), 6.04 (d, J=1.2 Hz, 1H), 4.51 (t, J=6.8 Hz, 2H), 3.89(s, 3H), 3.52 (t, J=5.84 Hz, 2H), 2.00 (m, 2H). ES-MS m/z 435 (MH⁺).Anal. Calcd. for C₂₃H₁₉ClN₄O₃: C, 63.53; H, 4.41; Cl, 8.16; N, 12.89.Found: C, 63.47; H, 4.28; N, 12.63; Cl, 8.49.

EXAMPLE 263-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-[(2-hydroxyethyl)methylamino]propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 79)

Pyridine (0.37 g, 4.62 mmol) and methanesulfonic anhydride (0.54 g, 3.08mmol) were added to Compound 74 (0.67 g, 1.54 mmol) in THF (10 mL). Themixture was heated at 50° C. for 2 h, then cooled to rt. Another portionof THF (5 mL) was added, followed by 1 N HCl (5 mL). The mixture wasstirred for another 15 min, then extracted with EtOAc several times. Thecombined EtOAc layers were washed once with 1 N HCl (10 mL), water (2×20mL) and saturated NaCl (20 mL), then dried (Na₂SO₄) and evaporated invacuo to obtain3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dioneas Compound 26a (0.73 g, 92%) as a reddish solid. ES-MS m/z 513 (MH⁺).

2-(methylaminino)ethanol (0.4 mL) was added to Compound 26a (0.1 g, 0.2mmol) in DMA (5 mL). The mixture was heated at 65° C. for 3 h, thencooled to rt. Water (5 mL) was added, then the mixture was extractedwith EtOAc (3×50 mL). The organic layers were combined, washed with H₂Oand brine, then dried (Na₂SO₄) and evaporated in vacuo to a dark oil.The oil was purified by flash column chromatography (96:4:0.4;DCM:MeOH:NH₄OH) to afford Compound 79 (25 mg, 25%) as an orange flakysolid. Compound 79 was dissolved in excess dilute HCl, then frozen andlyophilized to give the hydrochloride salt. ¹H NMR (CD₃OD) δ 8.01 (s,1H), 7.53 (d, J=8.6 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.29 (m, 1H), 7.21(d, J=8.7 Hz, 1H), 6.96 (s, 1H), 6.92 (m, 1H), 5.88 (d, J=1.9 Hz, 1H),4.33 (t, J=7.0 Hz, 2H), 3.75 (s, 3H), 3.47 (t, J=6.0 Hz, 2H), 2.33 (t,J=6.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.09 (s, 3H), 1.84 (m, 2H). ES-MSm/z 492 (MH⁺).

Using the procedure of Example 26 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 753-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-(1- 488pyrrolidinyl)propyl]-1H-indazol-3-yl]-1H- pyrrole-2,5-dione 763-[1-[3-(acetyloxy)propyl]-1H-indazol-3- 477yl]-4-(5-chloro-1-methyl-1H-indol-3-yl)-1H- pyrrole-2,5-dione 773-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3- 517(4-methyl-1-piperazinyl)propyl]-1H-indazol-3- yl]-1H-pyrrole-2,5-dione78 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-(4- 504morpholinyl)propyl]-1H-indazol-3-yl]-1H- pyrrole-2,5-dione 803-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3- 448(methylamino)propyl]-1H-indazol-3-yl]-1H- pyrrole-2,5-dione 823-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3- 538[methyl(phenylmethyl)amino]propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 273-[1-(2-naphthalenyl)-1H-indol-3-yl]-4-[1-[3-(1-pyrrolidinyl)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 85)

Following the procedure of Example 26, pyridine (0.7 g, 8.35 mmol) andmethanesulfonic anhydride (1.09 g, 6.26 mmol) were added to Compound 84(1.07 g, 2.09 mmol) (prepared in Example 24) in THF (20 mL). The mixturewas heated at 50° C. for 2 h, then cooled to rt. Another portion of THF(10 mL) was added, followed by addition of 1 N HCl (10 mL). The mixturewas stirred for 15 min, then extracted with EtOAc several times. Thecombined EtOAc layers were washed once with 1 N HCl (10 mL), water (2×20mL) and saturated NaCl (20 mL), then dried (Na₂SO₄) and evaporated invacuo to obtain a3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-napthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dioneanalog of Compound 26a (1.1 g, 92%) as a reddish solid. ES-MS m/z 591(MH⁺).

Pyrrolidine (1 mL) was added to the3-[1-[3-[(methylsulfonyl)oxy]propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(0.5 g, 0.975 mmol) in DMA (10 mL). The mixture was heated to 65° C. for3 h, then cooled to rt. Water (5 mL) was added, followed by extractionwith EtOAc (3×50 mL). The organic layers were combined, washed with H₂Oand brine, then dried (Na₂SO₄) and evaporated in vacuo to a dark brownoil. The oil was purified by flash column chromatography (97:3:0.3;DCM:MeOH:NH₄OH) to afford Compound 85 (0.1 g, 18%) as an orange flakysolid. Compound 85 was dissolved in excess dilute HCl, then frozen andlyophilized to give the hydrochloride salt. ¹H NMR (CD₃OD) δ 8.22 (s,1H), 8.01 (d, J=8.8 Hz, 1H), 7.89 (m, 3H), 7.49 (m, 7H), 7.00 (m, 2H),6.64 (t, J=7.5 Hz, 1H), 6.39 (d, J=8.1 Hz, 1H), 4.47 (t, J=6.2 Hz, 2H),3.44 (m, 2H), 3.07 (t, J=7.4 Hz, 2H), 2.82 (m, 2H), 2.16 (m, 2H), 1.93(m, 4H). ES-MS m/z 566 (MH⁺). Using the procedure of Example 27 and theappropriate reagents and starting materials known to those skilled inthe art, other compounds of the present invention may be preparedincluding, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 88 3-[1-[3-[(2-hydroxyethyl)methyl- 570amino]propyl]-1H-indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 893-[1-[3-(4-methyl-1-piperazinyl)propyl]-1H- 595indazol-3-yl]-4-[1-(2-naphthalenyl)-1H-indol- 3-yl]-1H-pyrrole-2,5-dione114 3-[1-[3-[(2-hydroxyethyl)methyl- 521amino]propyl]-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1193-[1-[3-(acetyloxy)propyl]-1H-indazol-3- 506yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H- pyrrole-2,5-dione

EXAMPLE 283-[1-(3-hydroxypropyl)-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 94)

Following the procedure of Example 25, the ester Compound 1c (2.4 g,8.56 mmol) and amide Compound 24b (2 g, 5.75 mmol) were combined in dryTHF (10 mL) under argon and cooled in an ice bath as 1 M potassiumt-butoxide in THF (28 mL, 28 mmol) was added with stirring over a 20 minperiod. After 40 min, the reaction was quenched in an ice bath, 12 N HCl(10 mL, 120 mmol) was slowly added over a 5 min period. The mixture wasstirred for 10 min and made basic to slightly basic with 3N NaOH, thenextracted with EtOAc. The organic layers were combined and washed withsaturated NaHCO₃ and brine, then dried (Na₂SO₄) and evaporated in vacuoto a flaky solid. The solid was purified by flash column chromatography(96:4:0.4; DCM:MeOH:NH₄OH) to afford Compound 94 (1.70 g, 64%) as anorange flaky solid. Compound 94 was dissolved in excess dilute HCl, thenfrozen and lyophilized to give the hydrochloride salt. ¹H NMR (CD₃OD) δ9.33 (s, 1H), 8.91 (m, 2H), 8.29 (m, 2H), 7.64 (m, 3H), 7.39 (t, J=7.4Hz, 1H), 7.19 (t, J=7.6 Hz, 1H), 7.08 (t, J=7.9 Hz, 1H), 6.77 (t, J=7.7Hz, 1H), 6.39 (d, J=7.9 Hz, 1H), 4.40 (t, J=6.3 Hz, 2H), 3.36 (t, J=5.6Hz, 2H), 1.80 (t, J=6.0 Hz, 2H). ES-MS m/z 464 (MH⁺). Anal. Calcd. forC₂₇H₂₁N₅O₃.1.3HCl.1.03H₂O (463.49/515.29): C, 61.26; H, 4.64; N, 13.23;Cl, 8.71; KF, 3.51. Found: C, 61.63; H, 4.64; N, 13.48; Cl, 9.13; KF,3.97.

Using the procedure of Example 28 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 1023-[1-(3-hydroxypropyl)-1H-indazol-3-yl]-4-[1- 464(2-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1053-[1-(3-hydroxypropyl)-1H-indazol-3-yl]-4-[1- 514(4-isoquinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5- dione 1063-[1-[2-(2-hydroxyethoxy)ethyl]-1H-indazol-3- 494yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H- pyrrole-2,5-dione 1103-[1-(2-hydroxyethyl)-1H-indazol-3-yl]-4-[1- 450(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione 1113-[1-(4-hydroxybutyl)-1H-indazol-3-yl]-4-[1- 478(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

EXAMPLE 293-(7-chloro-1-ethyl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 95)

Following the procedure of Example 4, using 7-chloroindole in place of5-chloroindole, 7-chloroindole (12.5 g, 0.082 mole) in a mixture withether (150 mL) was cooled in an ice bath and treated dropwise withoxalyl chloride (10.9 g, 0.086 mole) while stirring under argon. Theresulting yellow slurry was stirred at 5° C. for 30 min then cooled to−65° C. Anhydrous methanol (25 mL) was added dropwise to the coldmixture over a 30 min period. The mixture was allowed to warm to rt andwas stirred for 4 h. The resulting suspension of yellow solid wasfiltered and the solid washed with ether and air dried to give a7-chloroindole methyl ester analog of Compound 4b (13.6 g). The crudeproduct was used in the next step without further purification.

Following the procedure of Example 7, a mixture of the 7-chloroindolemethyl ester (3.0 g, 0.013 mole) and cesium carbonate (8.5 g, 0.026mole) in anhydrous DMF (75 mL) was stirred at 30° C. under argon for 1h. Iodoethane (9.8 g, 0.063 mole) was added dropwise and the mixture wasstirred overnight at 25-30° C. The reaction mixture was then dilutedwith ether (1 L) and partitioned with water (100 mL). The organic layerwas separated and the aqueous layer extracted with ether (200 mL). Thecombined organic layers were washed with brine, then dried overanhydrous sodium sulfate and concentrated in vacuo to give a N-ethylsubstituted 7-chloroindole methyl ester analog of Compound 7a (3.3 g) asa white solid. The solid was used in the next step without furtherpurification.

A mixture of Compound 1f (see Example 1) (170 mg, 0.65 mmol) and theN-ethyl substituted 7-chloroindole methyl ester (207 mg, 0.78 mmol) inanhydrous THF (6 mL) was stirred in an ice bath under argon. 1 Nsolution of potassium t-butoxide (2.6 mL) in THF was added to themixture dropwise while stirring under argon. The mixture was thenstirred for an additional 2.5 h at rt and then cooled in an ice bath andquenched with concentrated hydrochloric acid (1.5 mL). The mixture wasstirred for 15 min then partitioned with chloroform and saturated sodiumbicarbonate solution. The chloroform layer was washed with brine, thendried over anhydrous sodium sulfate and concentrated in vacuo to give anorange glass (334 mg). The orange glass was dissolved in a 90:10 mixtureof chloroform:methanol, then filtered through a plug of silica andstripped in vacuo to give a residual orange solid. The orange solid waspurified via reverse-phase HPLC using a gradient of 30%-100%acetonitrile/water (containing 0.2% TFA) to elute the product as a TFAsalt. The salt was freeze-dried to give Compound 95 (130 mg) as a fluffyorange solid. ¹H NMR (DMSO-d₆) δ 8.20 (s, 1H), 7.75 (d, 1H), 7.60 (d,1H), 7.40 (t, 1H), 7.15-7.05 (m, 2H), 6.70 (t, 1H), 6.35 (d, 1H), 4.65(q, 2H), 4.40 (t, 2H), 3.00 (m, 2H), 2.70 (s, 6H), 2.00 (m, 2H), 1.40(t, 3H). ES-MS m/z 476 (MH⁺). Anal. Calc'd for C₂₆H₂₆ClN₅O₂.1.15TFA.0.5H₂O: C, 55.17; H, 4.61; N, 11.37; F, 10.64, H₂O, 1.46. Found: C,55.36; H, 4.53; N, 11.42; F, 10.61; H₂O, 1.12.

EXAMPLE 303-[4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-2,5-dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1-ethyl-1H-indole-5-carbonitrile(Compound 98)

Following the procedure of Example 4, using 5-cyanoindole in place of5-chloroindole, 5-cyanoindole (13.7 g, 0.096 mole) in a mixture withether (200 mL) was cooled in an ice bath and treated dropwise withoxalyl chloride (12.7 g, 0.1 mole) while stirring under argon. Theresulting yellow slurry was stirred at 5° C. for 30 min then cooled to−65° C. Anhydrous methanol (25 mL) was added dropwise to the coldmixture over a 30 min period. The mixture was allowed to warm to rt andwas stirred for 4 h. The resulting suspension of yellow solid wasfiltered and the solid washed with ether and air-dried to give a5-cyanoindole methyl ester analog of Compound 4b (18.4 g). The crudeproduct was used in the next step without further purification.

Following the procedure of Example 7, a mixture of the 5-cyanoindolemethyl ester (2.97 g, 0.013 mole) and cesium carbonate (8.5 g, 0.026mole) in anhydrous DMF (75 mL) was stirred at 30° C. under argon for 1h. Iodoethane (9.8 g, 0.063 mole) was then added dropwise and themixture was stirred overnight at 25-30° C. The reaction mixture was thendiluted with ether (1 L) and partitioned with water (100 mL). Theorganic layer was separated and the aqueous layer extracted with ether(200 mL). The combined organic layers were washed with brine, then driedover anhydrous sodium sulfate and concentrated in vacuo to give aN-ethyl substituted 5-cyanoindole methyl ester analog of Compound 7a(1.7 g) as a white solid. The solid was used in the next step withoutfurther purification.

A mixture of Compound 1f (see Example 1) (170 mg, 0.65 mmol) and theN-ethyl substituted 5-cyanoindole methyl ester (207 mg, 0.78 mmol) inanhydrous THF (6 mL) was stirred in an ice bath under argon. 1 Nsolution of potassium t-butoxide (2.6 mL) in THF was added to themixture dropwise while stirring under argon. The mixture was thenstirred for an additional 2.5 h at rt and then cooled in an ice bath andquenched with concentrated hydrochloric acid (1.5 mL). The mixture wasstirred for 15 min then partitioned with chloroform and saturated sodiumbicarbonate solution. The chloroform layer was washed with brine, thendried over anhydrous sodium sulfate and concentrated in vacuo to give anorange glass. The orange glass was purified via reverse-phase HPLC usinga gradient of 30%-100% acetonitrile/water (containing 0.2% TFA) to elutethe product as a TFA salt. The salt was freeze-dried to give Compound 98(155 mg) as a fluffy orange solid. ¹H NMR (DMSO-d₆) δ 8.45 (s, 1H),7.80-7.70 (m, 2H), 7.55-7.40 (m, 3H), 7.10 (t, 1H), 6.70 (s, 1H), 4.50(t, 2H), 4.35 (q, 2H), 3.10 (m, 2H), 2.75 (s, 6H), 2.10 (m, 2H), 1.40(t, 3H). ES-MS m/z 467 (MH⁺). Anal. Calc'd. for C₂₇H₂₆N₆O₂.1.15TFA.0.5H₂O: C, 58.02; H, 4.65; N, 13.86; F, 10.81, H₂O, 1.48. Found: C,58.34; H, 4.76; N, 13.89; F, 10.72; H₂O, 1.58.

EXAMPLE 313-[1-[3-hydroxypropyl]-1H-indazol-3-yl]-4-[1-(3-quinolinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 107)

Following the procedure of Example 1, using 3-bromoquinoline in place of3-bromopyridine, a 1-(3-quinolinyl)-indol-3-yl glyoxylic methyl esteranalog of Compound 1c was prepared. ¹H NMR (CDCl₃) δ 9.15 (d, J=2.3 Hz,1H), 8.69 (s, 1H), 8.55 (d, J=7.1 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.28(d, J=8.5 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.87 (m, 1H), 7.72 (m, 1H),7.45 (m, 3H), 3.98 (s, 3H).

The quinolinyl ester (280 mg, 0.85 mmol) and amide Compound 24b (260 mg,0.75 mmol) were combined in THF (8.0 mL) with 1 M potassium t-butoxidein THF (3.0 mL, 3.0 mmol) at 0° C., addition of 12 N HCl gave an orangesolid (430 mg). The solid was purified using flash columnchromatography, first with an EtOAc system (EtOAc:MeOH; 50:1) and thenwith a DCM system (DCM:MeOH; 10:1) to afford Compound 107 (220 mg, 57%)as an orange solid. Compound 107 was dissolved in ACN (20 mL) and 0.25 Maqueous HCl (20 mL), then frozen and lyophilized to the hydrochloridesalt (220 mg). ES-MS m/z 514 (MH⁺). ¹H NMR (DMSO, 300 MHz) δ 9.23 (s,1H), 8.79 (s, 1H), 8.54 (s, 1H), 8.19 (d, J=8.3 Hz, 2H), 7.90 (m, 1H),7.75 (m, 3H), 7.63 (d, J=8.3 Hz, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 6.84(dd, J=7.2, 7.7 Hz, 1H), 6.58 (d, J=8.0 Hz, 1H), 4.42 (m, 2H), 3.25 (m,2H), 1.74 (m, 2H). Anal. Calcd. for C₃₁H₂₃N₅O₃.1.33HCl.3.0H₂O(513.55/616.09): C, 60.44; H, 4.96; N, 11.36; Cl, 7.65; KF, 8.76. Anal.Found: C, 60.41; H, 4.60; N, 11.08; Cl, 7.86; KF, 7.45.

EXAMPLE 323-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-4-[1-[3-(amino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 108)

Indazole Compound 1e (1.50 g, 8.6 mmol) in DMF (34 mL) was combined with1-(3-bromopropyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (3.64g, 13.0 mmol) and cesium carbonate (4.77, 14.6 mmol) and then placed inan oil bath at 65° C. for 2 h. After cooling to rt, the reaction wasfiltered, evaporated in vacuo and purified by flash columnchromatography (88:10:2; DCM:MeOH:NH₄OH) to afford Compound 32a (0.70 g,35%) as a pale yellow solid. ¹H NMR (CD₃OD) δ 7.75 (d, J=8.2 Hz, 1H),7.54 (d, J=8.5 Hz, 1H), 7.43-7.38 (m, 1H), 7.14 (t, J=7.2, 7.7 Hz, 1H),4.46 (t, J=6.7 Hz, 2H), 3.89 (s, 2H), 2.85-2.62 (m, 2H), 2.10-2.01 (m,2H). ES-MS m/z 233 (MH⁺).

The 1-(3-benzo[b]thienyl)-indol-3-yl glyoxylic methyl ester analog ofCompound 1c (prepared in Example 20) (302 mg, 0.90 mmol) and amideCompound 32a (150 mg, 0.64 mmol) were combined in dry THF (6 mL) undernitrogen and cooled in an ice bath as 1 M potassium t-butoxide in THF(2.6 mL, 2.6 mmol) was added with stirring over a 10 min period. After 2h, the reaction was quenched in an ice bath, 12N HCl (3.2 mL) was slowlyadded and the mixture was stirred for 10 min. The reaction was dilutedwith ethyl acetate (150 mL), washed with water (2×32 mL), saturatedNaHCO₃ (55 mL) and brine (55 mL), then dried (Na₂SO₄) and evaporated invacuo to a solid. The solid was purified by flash column chromatography(95:3:2; DCM:MeOH:NH₄OH) to afford a red solid Compound 108 (0.047 g,14%). The product was dissolved in 1 N HCl/CH₃CN (2:1), then frozen andlyophilized to give the hydrochloride salt of Compound 108. For Compound108: ¹H NMR (free base, CDCl₃) δ 8.29 (s, 1H), 7.95 (d, J=8.0 Hz, 1H),7.75 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 7.51-7.38 (m, 5H), 7.26-7.06 (m,3H), 6.82 (t, J=7.16, 7.92 Hz, 1H), 6.62 (d, J=8.03 Hz, 1H), 4.42 (t,J=6.72 Hz, 2H), 2.54 (t, J=6.79, 6.75 Hz, 2H), 1.87-1.81 (m, 2H). ES-MSm/z 518 (MH⁺). Anal. Calcd. for C₃₀H₂₃N₅O₂S.1.02HCl.1.5H₂O(517.60/581.83): C, 61.94; H, 4.69; N, 12.04; Cl, 6.22; KF, 4.65. Found:C, 61.97; H, 4.37; N, 11.95; Cl, 6.23; KF, 4.69.

Using the procedure of Example 32 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 115[3-[3-[2,5-dihydro-2,5-dioxo-4-[1-(3-pyridinyl)- 5631H-indol-3-yl]-1H-pyrrol-3-yl]-1H-indazol-1- yl]propyl]-carbamic acid1,1-dimethylethyl ester

EXAMPLE 333-[1-(3-aminopropyl)-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 109)

The ester Compound 1c (336 mg, 1.2 mmol) and amide Compound 32a(prepared in Example 32) (200 mg, 0.86 mmol) were combined in dry THF (8mL) under nitrogen and cooled in an ice bath as 1 M potassium t-butoxidein THF (3.4 mL, 3.4 mmol) was added with stirring over a 15 min period.After 1 h, the reaction was warmed to rt. After 2 h, the reaction wasquenched in an ice bath, 12N HCl (4.3 mL) was slowly added and themixture was stirred for 10 min. The reaction was diluted with ethylacetate (200 mL) and washed with water (2×43 mL), saturated NaHCO₃ (74mL) and brine (74 mL), then dried (Na₂SO₄) and evaporated in vacuo to asolid. The solid was purified by flash column chromatography (93:5:2;DCM:MeOH:NH₄OH) to afford Compound 109 (0.041 g, 10%) as a red solid.Compound 109 was dissolved in 1 N HCl:CH₃CN (2:1), then frozen andlyophilized to give the hydrochloride salt. ¹H NMR (free base, CDCl₃) δ8.89 (s, 1H), 8.70 (d, J=4.7 Hz, 1H), 8.25 (s, 1H), 7.91 (d, J=8.2 Hz,1H), 7.80 (d, J=8.2 Hz, 1H), 7.55-7.39 (m, 4H), 7.28-7.12 (m, 2H), 6.80(t, J=7.9, 7.2 Hz, 1H), 6.50 (d, J=8.0 Hz, 1H), 4.4 (t, J=6.7 Hz, 2H),2.55 (t, J=6.74 Hz, 2H), 1.79 (t, J=6.73, 6.78 Hz, 2H). ES-MS m/z 463(MH⁺). Anal. Calcd. for C₂₇H₂₂N₆O₂.2.23HCl.3.0H₂O (462.50/597.87): C,54.25; H, 5.10; N, 14.06; Cl, 13.23; KF, 9.04. Found: C, 54.25; H, 5.06;N, 13.86; Cl, 13.46; KF, 9.29.

EXAMPLE 34 1H-indazole-1-propanal,3-[2,5-dihydro-2,5-dioxo-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrol-3-yl]-1H-pyrrole-2,5-dione(Compound 112); 1H-indazole-1-propanoic acid,3-[2,5-dihydro-2,5-dioxo-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrol-3-yl]-1H-pyrrole-2,5-dione(Compound 113)

Dess-Martin reagent (0.34 g, 0.80 mmol) was added to Compound 94(prepared in Example 28) (0.31 g, 0.664 mmol) in CH₂Cl₂ (12 mL). Themixture was stirred at rt for 3 h, then another portion of Dess-Martinreagent (50 mg, 0.12 mmol) was added and the mixture was stirred for 1 huntil TLC showed that Compound 94 was no longer present. The reactionwas quenched with 25% Na₂S₂O₃ in water (3 mL). The aqueous layer wasextracted with chloroform several times. The organic layers werecombined and washed with water and brine, then dried (Na₂SO₄) andevaporated in vacuo to a reddish solid. The solid was purified by flashcolumn chromatography (95:5:0.5; DCM:MeOH:NH₄OH) to afford Compound 112(300 mg, 98%) as a red solid. ¹H NMR (CD₃OD) δ 9.43 (s, 1H), 8.84 (d,J=2.4 Hz, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.26 (s, 1H), 8.12 (m, 1H), 7.70(m, 1H), 7.61 (m, 2H), 7.43 (m, 2H), 7.14 (m, 2H), 6.75 (t, J=7.5 Hz,1H), 6.43 (d, J=8.1 Hz, 1H), 4.46 (t, J=6.9 Hz, 2H), 1.96 (m, 2H). ES-MSm/z 462 (MH⁺).

A small amount of crude Compound 113 (4 mg) was also isolated from thecolumn (using 75:20:5; DCM:MeOH:HOAc). Compound 113 was further purifiedby preparative TLC (95:5:0.5; DCM:MeOH:AcOH). ¹H NMR (DMSO) δ 8.90 (d,J=2.3 Hz, 1H), 8.70 (m, 1H), 8.41 (s, 1H), 8.14 (m, 1H), 7.67 (m, 2H),7.49 (d, J=8.3 Hz, 1H), 7.29 (m, 2H), 7.14 (m, 2H), 6.85 (t, J=7.6 Hz,1H), 6.55 (d, J=8.1 Hz, 1H), 4.54 (t, J=6.9 Hz, 2H), 2.58 (t, J=6.9 Hz,2H). ES-MS m/z 478 (MH⁺).

Using the procedure of Example 34 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 1163-[4-(1-benzo[b]thien-3-yl-1H-indol-3-yl)-2,5- 547dihydro-2,5-dioxo-1H-pyrrol-3-yl]-1H-indazole-1- propanoic acid methylester

EXAMPLE 353-[1-(3-methoxypropyl)-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 117)

Following the procedure for converting Compound 1e to Compound 1f, theindazole amide Compound 1e (0.31 g, 17.8 mmol) was treated with1-bromo-3-methoxypropane (0.3 g, 19.6 mmol) in the presence of 95% NaH(0.05 g, 19.6 mmol) in DMF (50 mL) at 0° C. for 20 min and then warmedto 60° C. for 2 h. The mixture was cooled down to rt. Water was addedand the aqueous solution was extracted with EtOAc several times. Theorganic layers were combined and washed with brine, then dried (Na₂SO₄)and evaporated in vacuo to an oil. The oil was purified by flash columnchromatography (96:4:0.4; DCM:MeOH:NH₄OH) to afford a 3-methoxypropylindazole amide analog of Compound 1f (0.32 g, 73%). ¹H NMR (CDCl₃) δ7.69 (d, J=8.13 Hz, 1H), 7.4 (m, 2H), 7.17 (m, 1H), 6.57 (bd s, 1H),5.39 (bd s, 1H), 4.47 (t, J=6.65 Hz, 2H), 3.96 (s, 2H), 3.30 (t, J=5.78Hz, 2H), 3.28 (s, 3H), 2.16 (m, 2H). ES-MS m/z 248 (MH⁺).

The ester Compound 1c (0.17 g, 0.61 mmol) and the 3-methoxypropylindazole amide (0.1 g, 0.4 mmol) were combined in dry THF (6 mL) underargon and cooled in an ice bath as 1 M potassium t-butoxide in THF (2mL, 2 mmol) was added with stirring over a 5 min period. After 40 min,the reaction was quenched in an ice bath, 12 N HCl (2 mL, 24 mmol) wasslowly added over a 2 min period. The mixture was stirred for 5 min andthen made basic to slightly basic by addition of 3N NaOH and extractedwith EtOAc. The organic layers were combined and washed with saturatedNaHCO₃ and brine, then dried (Na₂SO₄) and evaporated in vacuo to a flakysolid. The solid was purified by flash column chromatography (96:4:0.4;DCM:MeOH:NH₄OH) to afford Compound 117 (70 mg, 36%) as an orange flakysolid. Compound 117 was dissolved in excess dilute HCl, then frozen andlyophilized to give the hydrochloride salt. ¹H NMR (CD₃OD) δ 9.31 (s,1H), 8.90 (m, 2H), 8.36 (s, 1H), 8.24 (m, 1H), 7.73 (d, J=8.2 Hz, 1H),7.64 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.42 (t, J=7.1 Hz, 1H),7.20 (t, J=7.6 Hz, 1H), 7.12 (t, J=7.4 Hz, 1H), 6.78 (t, J=7.7 Hz, 1H),6.41 (d, J=8.1 Hz, 1H), 4.40 (t, J=6.6 Hz, 2H), 3.22 (s, 3H), 3.13 (t,J=5.9 Hz, 2H), 1.83 (m, 2H). ES-MS m/z 478 (MH⁺).

EXAMPLE 363-(1H-indazol-3-yl)-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione(Compound 118)

The ester Compound 1c (0.22 g, 0.8 mmol) and amide Compound 1e (0.1 g,0.57 mmol) were combined in dry THF (5 mL) under argon and cooled in anice bath as 1 M potassium t-butoxide in THF (2.9 mL, 2.9 mmol) was addedwith stirring over a 5 min period. After 40 min, the reaction wasquenched in an ice bath, 12 N HCl (2 mL, 24 mmol) was slowly added overa 5 min period. The mixture was stirred for 10 min and then made basicto slightly basic by addition of 3N NaOH and extracted with EtOAc. Theorganic layers were combined and wash with saturated NaHCO₃ and brine,then dried (Na₂SO₄) and evaporated in vacuo to a flaky solid. The solidwas purified by flash column chromatography (96:6:0.6; DCM:MeOH:NH₄OH)to afford Compound 118 (70 mg, 30%) as an orange flaky solid. Compound118 was dissolved in excess dilute HCl, then frozen and lyophilized togive the hydrochloride salt. ¹H NMR (CD₃OD) δ 9.3 (s, 1H), 8.88 (m, 2H),8.35 (s, 1H), 8.25 (m, 1H), 7.59 (m, 3H), 7.37 (t, J=6.9 Hz, 1H), 7.19(t, J=7.9 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 6.78 (t, J=7.8 Hz, 1H), 6.45(d, J=7.8 Hz, 1H). ES-MS m/z 406 (MH⁺).

Using the procedure of Example 36 and the appropriate reagents andstarting materials known to those skilled in the art, other compounds ofthe present invention may be prepared including, but not limited to:

ES-MS m/z Cpd Name (MH⁺) 1043-(1-(benzo[b]thien-3-yl-1H-indol-3-yl)-4-(1H- 461indazol-3-yl)-1H-pyrrole-2,5-dione

EXAMPLE 373-(6-chloro-1-ethyl-1H-indol-3-yl)-4-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione(Compound 90)

Following the procedure of Example 4, using 6-chloroindole in place of5-chloroindole, 6-chloroindole (10.5 g, 0.069 mole) in a mixture withether (150 mL) was cooled in an ice bath and treated dropwise withoxalyl chloride (9.2 g, 0.072 mole) while stirring under argon. Theresulting yellow slurry was stirred at 5° C. for 4 h then cooled to −65°C. Anhydrous methanol (25 mL) was added dropwise to the cold mixtureover a 30 min period, then the mixture was allowed to warm to rt and wasstirred for 4 h. The resulting suspension of yellow solid was filteredand the solid washed with ether and air-dried to give a 6-chloroindolemethyl ester analog of Compound 4b (15.8 g). The crude product was usedin the next step without further purification.

Following the procedure of Example 7, a mixture of the 6-chloroindolemethyl ester-(3.0 g, 0.013 mole) and cesium carbonate (8.5 g, 0.026mole) in anhydrous DMF (75 mL) was stirred at 30° C. under argon for 1h. Iodoethane (9.8 g, 0.063 mole) was then added dropwise and stirringcontinued at 25-30° C. overnight. The reaction mixture was then dilutedwith ether (1 L) and partitioned with water (100 mL). The organic layerwas separated and the aqueous layer extracted with ether (100 mL). Thecombined organic layers were washed with brine, then dried overanhydrous sodium sulfate and concentrated in vacuo to give a N-ethylsubstituted 6-chloroindole methyl ester analog of Compound 7a (3.5 g,100%) as a white solid. The solid was used in the next step withoutfurther purification.

A mixture of Compound 1f (see Example 1) (170 mg, 0.65 mmol) and theN-ethyl substituted 6-chloroindole methyl ester (207 mg, 0.78 mmol) inanhydrous THF (6 mL) was stirred in an ice bath under argon. Then a 1 Nsolution of potassium t-butoxide (2.6 mL) in THF was added dropwisewhile stirring under argon. The mixture was stirred for an additional2.5 h at rt, then cooled in an ice bath and quenched with concentratedhydrochloric acid (1.5 mL). The mixture was stirred for 15 min thenpartitioned with a chloroform and saturated sodium bicarbonate solution.The chloroform layer was washed with brine, then dried over anhydroussodium sulfate and concentrated in vacuo to give an orange glass. Theorange glass was purified via reverse-phase HPLC using a gradient of30%-90% acetonitrile/water (containing 0.2% TFA) to elute the product asa TFA salt. The salt was freeze-dried to give Compound 90 (45 mg) as afluffy orange solid. ¹H NMR (DMSO-d₆) δ 8.25 (s, 1H), 7.75 (d, 1H), 7.70(s, 1H), 7.60 (d, 1H), 7.40 (t, 1H), 7.15 (t, 1H), 6.75 (d, 1H), 6.25(d, 1H), 4.45 (t, 2H), 4.30 (q, 2H), 3.05 (m, 2H), 2.70 (2s, 6H), 2.00(m, 2H), 1.35 (t, 3H). ES-MS m/z 476 (MH⁺). Anal. Calc'd. forC₂₆H₂₆ClN₅O₂.1.0 TFA.0.7H₂O: C, 55.81; H, 4.75; N, 11.62; F, 9.46, H₂O,2.09. Found: C, 55.40; H, 4.51; N, 11.48; F, 9.66; H₂O, 1.48.

EXAMPLE 384-[1-[3-(dimethylamino)propyl]-1H-indazol-3-yl]-1,5-dihydro-3-[1-(3-pyridinyl)-1H-indol-3-yl]-2H-pyrrol-2-one(Compound 125)

The amide compound 1f (1.04 g, 4.0 mmol) and Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(0.97 g, 2.4 mmol) in dioxane (20 mL) was stirred at rt for 40 h.Additional Lawesson's reagent (0.97 g, 2.4 mmol) was added and themixture was stirred for another 3 h. The reaction was evaporated to anoil and purified by flash column chromatography (EtOAc:MeOH:NH₄OH;40:8:1) to give a thioamide Compound 38a (0.98 g, 89%) as a white solid.ES-MS m/z 277 (M⁺). ¹H NMR (CDCl₃) δ 7.73 (d, J=8.2 Hz, 1H), 7.45 (m,2H), 7.17 (m, 1H), 4.48 (s, 2H), 4.42 (dd, J=6.8, 6.8 Hz, 2H), 2.24 (m,2H), 2.20 (s, 6H), 2.06 (m, 2H).

Following the procedure of Example 1, the ester Compound 1c (1.1 g, 3.90mmol) and the thioamide Compound 38a (0.90 g, 3.26 mmol) were combinedwith 1 M potassium t-butoxide in THF (12.8 mL, 12.8 mmol) in THF (30 mL)to afford a thiomaleimide Compound 38b as a red-orange flaky solid (1.95g). Compound 38b was dissolved in THF (50 mL) and ethanol (20 mL) andRaney nickel (20 g) was added in portions, after washing first withethanol, and the mixture was stirred for another 30 min. The solutionwas decanted and evaporated in vacuo to afford Compound 125 as a lightorange solid. Compound 125 was purified by flash column chromatography(DCM:MeOH:NH₄OH; 80:8:1) to afford a light orange solid (0.28 g, 18%)that was dissolved in aqueous HCl, then frozen and lyophilized. ES-MSm/z 477 (M⁺). ¹H NMR (DMSO) δ 8.76 (d, J=1.4 Hz, 1H), 8.61 (dd, J=1.5,4.9 Hz, 1H), 7.83 (m, 1H), 7.72 (s, 1H), 7.48 (m, 3H), 7.15 (m, 3H),6.90 (m, 2H), 6.76 (dd, J=7.1, 7.4 Hz, 1H), 6.43 (s, 1H), 4.68 (s, 2H),4.45 (dd, J=6.8, 6.8 Hz, 2H), 2.23 (m, 2H), 2.20 (s, 6H), 2.04 (m, 2H).

EXAMPLE 39

As a specific embodiment of an oral composition, 100 mg of Compound 14is formulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0 hard gel capsule.

BIOLOGICAL EXPERIMENTAL EXAMPLES

The utility of the compounds to treat kinase or dual-kinase mediateddisorders (in particular, kinases selected from protein kinase C andglycogen synthase kinase-3; and, more particularly, kinases selectedfrom protein kinase C α, protein kinase C β-II, protein kinase C γ orglycogen synthase kinase-3β) was determined using the followingprocedures.

EXAMPLE 1 Protein Kinase C Histone-Based Assay

Compounds were evaluated for PKC selectivity using histone III as thesubstrate. The PKC isoforms α, β-II or γ were added to a reactionmixture that contained 20 mM HEPES, (pH 7.4), 940 μM CaCl₂, 10 mM MgCl₂,1 mM EGTA. 100 μg/mL phosphatidylserine, 20 μg/mL diacylglycerol, 30 μMATP, 1 μCi (³³P)ATP and 200 μg/mL histone III. The reaction wasincubated for 10 min at 30° C. Reactions were terminated by TCAprecipitation and spotting on Whatman P81 filters. Filters were washedin 75 mM phosphoric acid and the radioactivity quantified by liquidscintillation counting.

Table 1 shows the biological activity in the histone based assay as IC₅₀values (μM) for representative compounds of the present invention.

TABLE 1 PKC Activity (IC₅₀ μM, Histone Based Assay) Cpd Beta II AlphaGamma 1 0.014 0.052 0.058 3 0.023 0.248 0.323 6 0.013 0.105 0.129 90.008 0.141 0.262 12 0.007 0.124 0.213 13 0.004 0.011 0.045 14 0.0050.057 0.115 15 0.029 1.228 3.354 16 0.015 0.290 0.253 19 0.004 0.0110.047 22 0.006 0.043 0.090 23 0.054 0.546 0.188 24 0.029 0.200 1.290 310.015 0.106 0.091 34 0.009 0.205 0.665 45 0.010 0.071 0.168 46 0.0050.308 0.123 60 0.037 0.611 0.713 64 0.013 0.101 0.215 67 0.016 1.4830.650 68 0.011 0.217 0.426 69 0.014 0.250 0.550 70 0.018 0.259 0.342 750.010 0.204 0.175 77 0.046 0.354 0.890 78 0.016 0.940 0.530 79 0.0070.065 0.074 80 0.018 0.328 0.512 84 0.057 0.358 0.206 85 0.044 0.4770.511 88 0.038 0.422 0.232 94 0.011 0.306 0.411 101 0.019 0.080 0.134103 0.020 0.189 0.161 107 0.009 0.098 0.018 109 0.005 0.032 0.231 1140.004 0.047 0.038 117 0.034 — — 123 0.026 — — 125 0.005 0.339 —

EXAMPLE 2 Glycogen Synthase Kinase-3 Assay

Compounds were tested for the ability to inhibit recombinant rabbitGSK-3β protein using the following protocol. The test compound was addedto a reaction mixture containing Protein phosphatase inhibitor-2 (PPI-2)(Calbiochem)(45 ng), rabbit GSK-3β protein (New England Biolabs) (0.75units) and ³³P-ATP (1 μCi) in 50 mM Tris-HCl (pH 8.0), 10 mM MgCl₂, 0.1%BSA, 1 mM DTT and 100 μM Sodium Vanadate. The mixture was reacted for 90minutes at 30° C. to allow phosphorylation of the PPI-2 protein and thenthe protein in the reaction was precipitated using 10% TCA. Theprecipitated protein was collected on filter plates(MultiScreen-DV/Millipore), which were subsequently washed. Finally, theradioactivity was quantified using a TopCount Scintillation Counter(Packard). GSK-3 inhibitory compounds resulted in less phosphorylatedPPI-2 and thus a lower radioactive signal in the precipitated protein.Staurosporine or Valproate, known inhibitors of GSK-3β, were used as apositive control for screening.

Table 2 shows the biological activity in the GSK-3β assay as IC₅₀ values(μM) for representative compounds of the present invention.

TABLE 2 GSK-3β Assay Activity (IC₅₀ μM) Cpd GSK-3β 1 0.090 3 0.049 40.270 6 0.048 32 0.510 33 0.070 43 0.034 46 0.010 48 0.090 68 0.096 690.018 74 0.014 75 0.033 76 0.085 77 0.043 78 0.041 79 0.014 80 0.051 860.130 90 0.096 94 0.058 95 0.060 98 0.015 102 0.210 105 0.073 106 0.033107 0.820 110 0.075 111 0.040 112 0.115 114 0.155 115 0.055 117 0.070118 0.200

The results from the foregoing indicate that a compound of the presentinvention would be expected to be useful in treating or ameliorating akinase or dual-kinase mediated disorder.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of Formula (I):

wherein R¹ and R² are independently selected from the group consistingof: hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl {wherein alkyl,alkenyl and alkynyl are optionally substituted with one to twosubstituents independently selected from the group consisting of—O—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-OH, —O—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl,—O—(C₁₋₈)alkyl-NH₂, —O—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl,—O—(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂, —O—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl,—O—(C₁₋₈)alkyl-SO₂—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-SO₂—NH_(2,)—O—(C₁₋₈)alkyl-SO₂—NH—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-SO₂—N[(C₁₋₈)alkyl]₂,—O—C(O)H, —O—C(O)—(C₁₋₈)alkyl, —O—C(O)—NH₂, —O—C(O)—NH—(C₁₋₈)alkyl,—O—C(O)—N[(C₁₋₈)alkyl]₂, —O—(C₁₋₈)alkyl—C(O)H,—O—(C₁₋₈)alkyl-C(O)—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-CO₂H,—O—(C₁₋₈)alkyl-C(O)—O—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-C(O)—NH_(2,)—O—(C₁₋₈)alkyl-C(O)—NH—(C₁₋₈)alkyl, —O—(C₁₋₈)alkyl-C(O)—N[(C₁₋₈)alkyl]₂,—C(O)H, —C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,—C(NH)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SH,—S—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-OH,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH₂,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl,—S—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,—S—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-OH,—(C₁₋₈)alkyl-O—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-NH₂,—(C₁₋₈)alkyl-NH—(C₁₋₈)alkyl, —(C₁₋₈)alkyl-N[(C₁₋₈)alkyl]₂,—(C₁₋₈)alkyl-S—(C₁₋₈)alkyl, —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl,—C(O)—NH₂, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂,—SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂,—C(N)—NH₂, aryl and aryl(C₁₋₈)alkyl (wherein aryl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, C₁₋₈alkyl, C₁₋₈alkoxy, amino(substituted with two substituents selected from the group consisting ofhydrogen and C₁₋₈alkyl), cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl,(halo)₁₋₃(C₁₋₈)alkoxy, hydroxy, hydroxy(C₁₋₈)alkyl and nitro)), cyano,(halo)₁₋₃, hydroxy, nitro, oxo, heterocyclyl, aryl and heteroaryl(wherein heterocyclyl, aryl and heteroaryl are optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₈alkyl, C₁₋₈alkoxy, amino (substituted with twosubstituents selected from the group consisting of hydrogen andC₁₋₈alkyl), cyano, halo, (halo)₁₋₃(C₁₋₈)alkyl, (halo)₁₋₃(C₁₋₈)alkoxy,hydroxy, hydroxy(C₁₋₈)alkyl and nitro)}, —C(O)—(C₁₋₈)alkyl, —C(O)-aryl,—C(O)—O—(C₁₋₈)alkyl, —C(O)—O-aryl, —C(O)—NH—(C₁₋₈)alkyl, —C(O)—NH-aryl,—C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl, —SO₂-aryl, aryl and heteroaryl{wherein aryl and heteroaryl are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, —C(O)H,—C(O)—(C₁₋₈)alkyl, —CO₂H, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂,—C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SH, —S—(C₁₋₈)alkyl,—SO₂—(C₁₋₈)alkyl, —SO₂—NH_(2,) —SO₂—NH—(C₁₋₈)alkyl,—SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with two substituentsindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂, —C(O)—(C₁₋₈)alkyl,—C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(O)—NH—(C₁₋₈)alkyl,—C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH_(2,)—SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂),amino-(C₁₋₈)alkyl-(wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂, —C(O)—(C₁₋₈)alkyl,—C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(O)—NH—(C₁₋₈)alkyl,—C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₈)alkyl,—SO₂—N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂), cyano, halo,(halo)₁₋₃(C₁₋₈)alkyl-, (halo)₁₋₃(C₁₋₈)alkoxy-, hydroxy,hydroxy(C₁₋₈)alkyl, nitro, aryl, —(C₁₋₈)alkyl-aryl,heteroaryl and—(C₁₋₈)alkyl-heteroaryl}; with the proviso that if R² is selected fromthe group consisting of hydrogen, unsubstituted C₁₋₇alkyl and—(C₁₋₇)alkyl-(halo)₁₋₃, then R¹ is selected from the group consisting ofother than hydrogen, C₁₋₇alkyl, aryl (limited to phenyl unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of halo, unsubstituted C₁₋₇alkyl, hydroxy, unsubstitutedC₁₋₇alkoxy, (halo)₁₋₃(C₁₋₇)alkyl, nitro, unsubstituted amino and cyano),—(C₁₋₇)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of halo, unsubstituted C₁₋₇alkyl, hydroxy, C₁₋₇alkoxy,(halo)₁₋₃(C₁₋₇)alkyl, nitro, unsubstituted amino and cyano),—(C₁₋₇)alkyl(C₁₋₇)alkoxy, —(C₁₋₇)alkyl-hydroxy, —(C₁₋₇)alkyl-(halo)₁₋₃,—(C₁₋₇)alkyl-amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen and(C₁₋₇alkyl), —(C₁₋₇)alkyl-amino(C₁₋₇)alkylamino,—C₁₋₇alkyl-NH—C(O)—(C₁₋₇)alkyl, —C₁₋₇alkyl-NH—SO₂—(C₁₋₇)alkyl,—(C₁₋₇)alkyl-SH, —(C₁₋₇)alkyl-S—(C₁₋₇)alkyl,—(C₁₋₇)alkyl-SO₂—(C₁₋₇)alkyl, —(C₁₋₇)alkyl-O—C(O)—(C₁₋₇)alkyl,—(C₁₋₇)alkyl-C(N), —(C₁₋₇)alkyl-C(NH)—NH₂, —(C₁₋₇)alkyl-CO₂H,—(C₁₋₇)alkyl-C(O)—O—(C₁₋₇)alkyl, —(C₁₋₇)alkyl-C(O)—NH₂,—(CH₂)₂₋₆-heterocyclyl, —(CH ₂)₂₋₆—T-C(V)-Z (wherein T is NH, V is O andZ is amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₇alkyl)); with the provision that for R¹ and R² heteroaryl shall meanpyridinyl, quinolinyl orisoquinolinyl; X is N; R³ and R⁴ areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, —C(O)H, —C(O)—(C₁₋₈)alkyl, —CO₂H,—C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(NH)—NH₂, —C(O)—NH—(C₁₋₈)alkyl,—C(O)—N[(C₁₋₈)alkyl]₂, —SH, —S—(C₁₋₈)alkyl, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₈)alkyl, —SO₂—N[(C₁₋₈)alkyl]₂, amino (substituted with twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —(C₁₋₈)alkyl-NH₂,—C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂, —C(O)—NH—(C₁₋₈)alkyl,—C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂, —SO₂ —NH—(C₁₋₈)alkyl,—SO₂ —N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂), amino-(C₁₋₈)alkyl-(wherein aminois substituted with two substituents independently selected from thegroup consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,—(C₁₋₈)alkyl-NH₂, —C(O)—(C₁₋₈)alkyl, —C(O)—O—(C₁₋₈)alkyl, —C(O)—NH₂,—C(O)—NH—(C₁₋₈)alkyl, —C(O)—N[(C₁₋₈)alkyl]₂, —SO₂—(C₁₋₈)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₈)alkyl, —SO₂ —N[(C₁₋₈)alkyl]₂ and —C(NH)—NH₂), cyano, halo,(halo)₁₋₃(C₁₋₈)alkyl-, (halo)₁₋₃(C₁₋₈)alkoxy-, hydroxy,hydroxy(C₁₋₈)alkyl-, nitro, aryl, and —(C₁₋₈)alkyl-aryl; and, Y and Zare independently selected from the group consisting of O, S, (H,OH) and(H,H); with the proviso that one of Y and Z is O and the other isselected from the group consisting of O, S, (H,OH) and (H,H); andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1wherein R¹ and R² are independently selected from the group consistingof: hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl {wherein alkyl,alkenyl and alkynyl are optionally substituted with one to twosubstituents independently selected from the group consisting of—O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-NH₂, —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-N[(C₁₋₄)alkyl]₂, —O—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-SO₂—NH₂,—O—(C₁₋₄)alkyl-SO₂—NH—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-SO₂—N[(C₁₋₄)alkyl]₂,—O—C(O)H, —O—C(O)—(C₁₋₄)alkyl, —O—C(O)—NH₂, —O—C(O)—NH—(C₁₋₄)alkyl,—O—C(O)—N[(C₁₋₄)alkyl]₂, —O—(C₁₋₄)alkyl-C(O)H,—O—(C₁₋₄)alkyl-C(O)—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-CO₂H,—O—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl,—O—(C₁₋₄)alkyl-C(O)—NH₂,—O—(C₁₋₄)alkyl-C(O)—NH—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-C(O)—N[(C₁₋₄)alkyl]₂,—C(O)H, —C(O)—(C₁₋₄)alkyl, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,—C(NH)—NH₂, —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SH,—S—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-OH,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH₂,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,—S—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl-N[(C₁₋₄)alkyl]₂,—S—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂, amino (substituted with twosubstituents independently selected from the group consisting ofhydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-OH,—(C₁₋₄)alkyl-O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-NH₂,—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-N[(C₁₋₄)alkyl]₂,—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl,—C(O)—NH₂, —C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂,—SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂,—C(N)—NH₂, aryl and aryl(C₁₋₄)alkyl (wherein aryl is optionallysubstituted with one to three substituents independently selected fromthe group consisting of halogen, C₁₋₄alkyl, C₁₋₄alkoxy, amino(substituted with two substituents selected from the group consisting ofhydrogen and C₁₋₄alkyl), cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl,(halo)₁₋₃(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl and nitro)), cyano,(halo)₁₋₃, hydroxy, nitro, oxo, heterocyclyl, aryl and heteroaryl(wherein heterocyclyl, aryl and heteroaryl are optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino (substituted with twosubstituents selected from the group consisting of hydrogen andC₁₋₄alkyl), cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy,hydroxy, hydroxy(C₁₋₄)alkyl and nitro)}, —C(O)—(C₁₋₄)alkyl, —C(O)-aryl,—C(O)—O—(C₁₋₄)alkyl, —C(O)—O-aryl, —C(O)—NH—(C₁₋₄)alkyl, —C(O)—NH-aryl,—C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂-aryl, aryl and heteroaryl{wherein aryl and heteroaryl are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, —C(O)H,—C(O)—(C₁₋₄)alkyl, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂,—C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SH, —S—(C₁₋₄)alkyl,—SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂,amino (substituted with two substituents independently selected from thegroup consisting of hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,—(C₁₋₄)alkyl-NH₂, —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,—C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂),amino-(C₁₋₄)alkyl- (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-NH₂, —C(O)—(C₁₋₄)alkyl,—C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(O)—NH—(C₁₋₄)alkyl,—C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl,—SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂), cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl,(halo)₁₋₃(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, nitro, aryl,—(C₁₋₄)alkyl-aryl, heteroaryl and —(C₁₋₄)alkyl-heteroaryl}; with theproviso that if R² is selected from the group consisting of hydrogen,unsubstituted C₁₋₄alkyl and —(C₁₋₄)alkyl-(halo)₁₋₃, then R¹ is selectedfrom the group consisting of other than hydrogen, C₁₋₄alkyl, aryl(limited to phenyl unsubstituted or substituted with one or moresubstituents selected from the group consisting of halo, unsubstitutedC₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro,unsubstituted amino and cyano), —(C₁₋₄)alkyl-aryl (wherein aryl islimited to phenyl unsubstituted or substituted with one or moresubstituents selected from the group consisting of halo,unsubstitutedC₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl,nitro, unsubstituted amino and cyano), —(C₁₋₄)alkyl(C₁₋₄)alkoxy,—(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-amino(wherein amino is substituted with two substituents independentlyselected from the group consisting of hydrogen and —C₁₋₄alkyl),—(C₁₋₄)alkyl-amino(C₁₋₄)alkylamino, —C₁₋₄alkyl-NH—C(O)—(C₁₋₄)alkyl,—C₁₋₄alkyl-NH—SO₂—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SH,—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,—(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(N),—(C₁₋₄)alkyl-C(NH)—NH₂, —(C₁₋₄)alkyl-CO₂H,—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(O)—NH₂,—(CH₂)₂₄-heterocyclyl, —(CH₂)₂₋₄-T-C(V)-Z (wherein T is NH, V is O and Zis amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl)) with the provision that for R¹ and R² heteroaryl shall meanpyridinyl, quinolinyl or isoquinolinyl.
 3. The compound of claim 1wherein R¹ and R² are independently selected from the group consistingof: hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl {wherein alkyl is substituted withone to two substituents independently selected from the group consistingof —O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,—O—C(O)—(C₁₋₄)alkyl, —C(O)H, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, amino(substituted with two substituents independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —(C₁₋₄)alkyl-OH, —C(O)—O—(C₁₋₄)alkyland aryl(C₁₋₄)alkyl), hydroxy, heterocyclyl, aryl and heteroaryl(wherein heterocyclyl, aryl and heteroaryl are optionally substitutedwith one to three substituents independently selected from the groupconsisting of C₁₋₄alkyl and halo)}, aryl and heteroaryl {wherein aryland heteroaryl are optionally substituted with one to two substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, amino (substituted with two substituents independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl), cyano,halo, (halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,hydroxy(C₁₋₄)alkyl, aryl and heteroaryl}; with the proviso that if R² isselected from the group consisting of hydrogen and unsubstitutedC₁₋₄alkyl, then R¹ is selected from the group consisting of other thanhydrogen, C₁₋₄alkyl, aryl (limited to phenyl unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of halo, unsubstituted C₁₋₄alkyl, hydroxy, C₁₋₄alkoxy,(halo)₁₋₃(C₁₋₄)alkyl, unsubstituted amino and cyano), —(C₁₋₄)alkyl-aryl(wherein aryl is limited to phenyl unsubstituted or substituted with oneor more substituents selected from the group consisting of halo andunsubstituted C₁₋₄alkyl), —(C₁₋₄)alkyl(C₁₋₄)alkoxy,—(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-amino (wherein amino is substitutedwith two substituents independently selected from the group consistingof hydrogen and—C₁₋₄alkyl), —(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl,—(C₁₋₄)alkyl-CO₂H, —(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl and—(CH₂)₂₄-heterocyclyl; with the provision that for R¹ and R² heteroarylshall mean pyridinyl, quinolinyl or isoquinolinyl.
 4. The compound ofclaim 1 wherein R¹ is selected from the group consisting of: hydrogen,C₁₋₄alkyl, C₂₋₄alkenyl {wherein alkyl is substituted with one to twosubstituents independently selected from the group consisting of—O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, amino (substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl), hydroxy, heterocyclyl, aryl and heteroaryl (whereinheterocyclyl, aryl and heteroaryl are optionally substituted with one tothree substituents independently selected from the group consisting ofC₁₋₄alkyl and halo)}, aryl and heteroaryl (wherein aryl and heteroarylare optionally substituted with one to two substituents independentlyselected from the group consisting of C₁₋₄alkyl, C₁₋₄alkoxy, amino(substituted with two substituents independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl), cyano, halo,(halo)₁₋₃(C₁₋₄)alkyl, (halo)₁₋₃(C₁₋₄)alkoxy, hydroxy,hydroxy(C₁₋₄)alkyl, aryl and heteroaryl}; with the proviso that if R² isselected from the group consisting of hydrogen, unsubstituted C₁₋₄alkyland —(C₁₋₄)alkyl-(halo)₁₋₃, then R¹ is selected from the groupconsisting of other than hydrogen, C₁₋₄alkyl, aryl (limited to phenylunsubstituted or substituted with one or more substituents selected fromthe group consisting of halo, unsubstituted C₁₋₄alkyl, hydroxy,C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, unsubstituted amino and cyano),—(C₁₋₄)alkyl-aryl (wherein aryl is limited to phenyl unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of halo and unsubstituted C₁₋₄alkyl), —(C₁₋₄)alkyl-hydroxy,—(C₁₋₄)alkyl-amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl) and —(CH₂)₂₄-heterocyclyl; with the provision that for R¹ andR² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl.
 5. Thecompound of claim 1 wherein R¹ is selected from the group consisting of:hydrogen, C₁₋₄alkyl, C₂₋₃alkenyl {wherein alkyl is substituted with oneto two substituents independently selected from the group consisting of—O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, amino (substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl), hydroxy, pyrrolidinyl, morpholinyl, piperazinyl (whereinpiperazinyl is optionally substituted with methyl), phenyl, naphthalenyland quinolinyl (wherein phenyl and benzo[b]thienyl are optionallysubstituted with one to two chloro substituents)}, phenyl, naphthalenyl,pyridinyl, quinolinyl and isoquinolinyl (wherein phenyl, naphthalenyland pyridinyl are optionally substituted with one to two substituentsindependently selected from the group consisting of C₁₋₄alkyl,C₁₋₄alkoxy, halo and hydroxy; and, wherein phenyl is optionallysubstituted with one substituent selected from the group consisting ofphenyl and thienyl); with the proviso that if R² is selected from thegroup consisting of hydrogen, unsubstituted C₁₋₄alkyl and—(C₁₋₄)alkyl-(halo)₁₋₃, then R¹ is selected from the group consisting ofother than hydrogen, C₁₋₄alkyl, phenyl (wherein phenyl is unsubstitutedor substituted with one or more substituents selected from the groupconsisting of halo, unsubstituted C₁₋₄alkyl, hydroxy and C₁₋₄alkoxy),—(C₁₋₄)alkyl-phenyl (wherein phenyl is unsubstituted or substituted withone or more chloro substituents), —(C₁₋₄)alkyl-hydroxy,—(C₁₋₄)alkyl-amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl) and —(CH₂)₂₋₄-heterocyclyl; with the provision that for R¹and R² heteroaryl shall mean pyridinyl, quinolinyl or isoquinolinyl. 6.The compound of claim 1 wherein R² is selected from the group consistingof: hydrogen, C₁₋₄alkyl {wherein alkyl is substituted with one to twosubstituents independently selected from the group consisting of—O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-OH, —O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl,—O—C(O)—(C₁₋₄)alkyl, —C(O)H, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, amino(substituted with two substituents independently selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —(C₁₋₄)alkyl-OH, —C(O)—O—(C₁₋₄)alkyland aryl(C₁₋₄)alkyl), hydroxy and heterocyclyl (wherein heterocyclyl isoptionally substituted with one to two C₁₋₄alkyl substituents)} andheteroaryl; with the proviso that if R² is selected from the groupconsisting of hydrogen and unsubstituted C₁₋₄alkyl, then R¹ is selectedfrom the group consisting of other than hydrogen, C₁₋₄alkyl, aryl(limited to phenyl unsubstituted or substituted with one or moresubstituents selected from the group consisting of halo, unsubstitutedC₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro,unsubstituted amino and cyano), —(C₁₋₄)alkyl-aryl (wherein aryl islimited to phenyl unsubstituted or substituted with one or moresubstituents selected from the group consisting of halo, unsubstitutedC₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro,unsubstituted amino and cyano), —(C₁₋₄)alkyl(C₁₋₄)alkoxy,—(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-amino(wherein amino is substituted with two substituents independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl),—(C₁₋₄)alkyl-amino(C₁₋₄)alkylamino, —C₁₋₄alkyl-NH—C(O)—(C₁₋₄)alkyl,—C₁₋₄alkyl-NH—SO₂—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SH,—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,—(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(N),—(C₁₋₄)alkyl-C(NH)—NH₂, —(C₁₋₄)alkyl-CO₂H,—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(O)—NH₂,—(CH₂)₂₄-heterocyclyl, —(CH₂)₂₋₄-T-C(V)-Z (wherein T is NH, V is O and Zis amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl)); with the provision that for R¹ and R² heteroaryl shall meanpyridinyl, quinolinyl or isoquinolinyl.
 7. The compound of claim 1wherein R² is selected from the group consisting of: hydrogen, C₁₋₄alkyl{wherein alkyl is substituted with one to two substituents independentlyselected from the group consisting of —O—(C₁₋₄)alkyl, —O—(C₁₋₄)alkyl-OH,—O—(C₁₋₄)alkyl-NH—(C₁₋₄)alkyl, —O—C(O)—(C₁₋₄)alkyl, —C(O)H,—CO₂H,—C(O)—O—(C₁₋₄)alkyl, amino (substituted with two substituentsindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,—(C₁₋₄)alkyl-OH, —C(O)—O—(C₁₋₄)alkyl and phenyl(C₁₋₄)alkyl), hydroxy,pyrrolidinyl, 1,3-dioxolanyl, morpholinyl and piperazinyl (whereinpiperazinyl is optionally substituted with methyl)} and pyridinyl; withthe proviso that if R² is selected from selected from the groupconsisting of hydrogen and unsubstituted C₁₋₄alkyl, then R¹ is selectedfrom the group consisting of other than hydrogen, C₁₋₄alkyl, aryl(limited to phenyl unsubstituted or substituted with one or moresubstituents selected from the group consisting of halo, unsubstitutedC₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro,unsubstituted amino and cyano), —(C₁₋₄)alkyl-aryl (wherein aryl islimited to phenyl unsubstituted or substituted with one or moresubstituents selected from the group consisting of halo, unsubstitutedC₁₋₄alkyl, hydroxy, C₁₋₄alkoxy, (halo)₁₋₃(C₁₋₄)alkyl, nitro,unsubstituted amino and cyano), —(C₁₋₄)alkyl(C₁₋₄)alkoxy,—(C₁₋₄)alkyl-hydroxy, —(C₁₋₄)alkyl-(halo)₁₋₃, —(C₁₋₄)alkyl-amino(wherein amino is substituted with two substituents independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl),—(C₁₋₄)alkyl-amino(C₁₋₄)alkylamino, —C₁₋₄alkyl-NH—C(O)—(C₁₋₄)alkyl,—C₁₋₄alkyl-NH—SO₂—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SH,—(C₁₋₄)alkyl-S—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-SO₂—(C₁₋₄)alkyl,—(C₁₋₄)alkyl-O—C(O)—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(N),—(C₁₋₄)alkyl-C(NH)—NH₂, —(C₁₋₄)alkyl-CO₂H,—(C₁₋₄)alkyl-C(O)—O—(C₁₋₄)alkyl, —(C₁₋₄)alkyl-C(O)—NH₂,—(CH₂)₂₄-heterocyclyl, —(CH₂)₂₄-T-C(V)-Z (wherein T is NH, V is O and Zis amino (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen andC₁₋₄alkyl)); with the provision that for R¹ and R² heteroaryl shall meanpyridinyl, quinolinyl or isoquinolinyl.
 8. The compound of claim 1wherein R³ and R⁴ are independently selected from the group consistingof hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, —C(O)H,—C(O)—(C₁₋₄)alkyl, —CO₂H, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(NH)—NH₂,—C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SH, —S—(C₁₋₄)alkyl,—SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂,amino (substituted with two substituents independently selected from thegroup consisting of hydrogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,—(C₁₋₄)alkyl-NH₂, —C(O)—(C₁₋₄)alkyl, —C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂,—C(O)—NH—(C₁₋₄)alkyl, —C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂,—SO₂—NH—(C₁₋₄)alkyl, —SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂),amino-(C₁₋₄)alkyl- (wherein amino is substituted with two substituentsindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, —(C₁₋₄)alkyl-NH₂, —C(O)—(C₁₋₄)alkyl,—C(O)—O—(C₁₋₄)alkyl, —C(O)—NH₂, —C(O)—NH—(C₁₋₄)alkyl,—C(O)—N[(C₁₋₄)alkyl]₂, —SO₂—(C₁₋₄)alkyl, —SO₂—NH₂, —SO₂—NH—(C₁₋₄)alkyl,—SO₂—N[(C₁₋₄)alkyl]₂ and —C(NH)—NH₂), cyano, halo, (halo)₁₋₃(C₁₋₄)alkyl,(halo)₁₋₃(C₁₋₄)alkoxy, hydroxy, hydroxy(C₁₋₄)alkyl, nitro, aryl, and—(C₁₋₄)alkyl-aryl.
 9. The compound of claim 1 wherein R³ and R⁴ areindependently selected from the group consisting of hydrogen, C₁₋₄alkyl,C₁₋₄alkoxy, cyano and halogen.
 10. The compound of claim 1 wherein R³and R⁴ are independently selected from the group consisting of hydrogen,methyl, methoxy, cyano and chloro.
 11. The compound of claim 1 wherein Yand Z are independently selected from the group consisting of O and(H,H); with the proviso that one of Y and Z is O, and the other isselected from the group consisting of O and (H,H).
 12. The compound ofclaim 1 wherein the compound of Formula (I) is a compound selected fromFormula (Ic):

Formula (Ic) wherein X, R¹, R², R³, R⁴ and R⁵ are dependently selectedfrom the group consisting of: X R¹ R² R³ R⁴ R⁵ N H₂C═CHCH₂N1—[Me₂N(CH₂)₃] H H —; N H N1—[Me₂N(CH₂)₃] H H —; and, N Me₂N(CH₂)₃N1—[Me₂N(CH₂)₃] H H —; and pharmaceutically acceptable salts thereof.


13. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.